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Lipid-based Nanoparticles: Strategy for Targeted Cancer Therapy

Ashish Singh Chauhan^1,*, Pallavi Chand^1,* and Tarun Parashar²

¹Department of Pharmaceutics, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand, India

²School of Pharmacy & Research, Dev Bhoomi Uttarakhand University, Dehradun-248007, Uttarakhand, India

*Correspondence to: Ashish Singh Chauhan, Department of Pharmaceutics, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand, India, Contact No.: +91 8439209135. E-mail: ashishchauhan.pharmacy@gmail.com; Pallavi Chand, Department of Pharmaceutics, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand, India, Contact No.: +91 8979302352. E-mail: pallavichand1990@gmail.com

Received: October 7 2024; Revised: November 24 2024; Accepted: January 30 2025; Published Online: April 4 2025

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Cite this paper:

Chauhan AS, Chand P, Parashar T. Lipid-based Nanoparticles: Strategy for Targeted Cancer Therapy. BIO Integration 2025; 6: 1–23.

DOI: 10.15212/bioi-2024-0107. Available at: https://bio-integration.org/

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© 2025 The Authors. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See https://bio-integration.org/copyright-and-permissions/

Abstract

Lipid-based Nanoparticles (LBNPs) have emerged as a transformative approach in cancer treatment, offering innovative drug delivery solutions that enhance therapeutic efficacy while minimizing adverse effects. By exploring the characterization, classification, synthesis, targeting strategies, and advantages of LBNPs, this study highlights how LBNPs have been used to overcome the limitations of traditional chemotherapy and improve patient outcomes. As nanotechnology revolutionizes cancer therapy, the emergence of LBNPs as a promising strategy for targeted drug delivery has led to optimism regarding the future of cancer treatment. This review extensively assesses the structure, categories, production methods, targeting strategies, benefits, and recent advancements in LBNPs for treating cancer. It also highlights current challenges and possible future directions. This review is aimed at providing a comprehensive understanding of LBNPs’ potential in cancer therapy. Liposomes, nanostructured lipid carriers, solid lipid nanoparticles, and lipid-polymer hybrid nanoparticles are all types of LBNPs, each with unique features of interest for cancer therapy. These particles can be synthesized through various procedures, such as bulk nanoprecipitation, solvent-based emulsification, or microfluidics. Passive targeting systems, active targeting systems, and responsive delivery platforms direct LBNPs to tumors. Consequently, LBNPs provide an improved drug release pattern that minimizes side effects while enhancing therapeutic efficacy. With the potential for combination therapy, LBNPs offer a hopeful future for cancer treatment. Continued research is expected to improve patient outcomes and overall quality of life in cancer care.

Keywords

cancer nano therapy, LBNPs, targeted drug delivery.

Introduction

Cancer is a broad category of diseases occurring when abnormal cells grow uncontrollably in any organ or tissue of the body, cross their usual boundaries and invade adjoining parts of the body, and spread to other organs. The late cancer phase known as metastasis is a primary cause of cancer-related death. Cancers are sometimes called neoplasms or malignant tumors [1]. In 2023, cancer was the second leading cause of death worldwide. The Pan American Health Organization/World Health Organization have reported an estimated 10 million global cancer fatalities in 2023 and projected 20 million new cases by 2024 [2]. Men have a relatively higher risk of developing lung, colorectal, stomach, prostate, and liver cancer, whereas women have a relatively higher likelihood of developing cervical, thyroid, breast, colorectal, and lung cancer [3]. Studies on lipid-based nanoparticles (LBNPs) for cancer therapy have incorporated several United Nations sustainable development goals (SDGs), including the third SDG (good health and well-being). Thus, this review is aimed at helping to enhance the effectiveness and safety of cancer therapy using LBNPs for anticancer medication treatment, thereby improving health and well-being, and achieving SDG 9 (industry, innovation, and infrastructure). The use and development of LBNPs involves advanced nanotechnology, and basic pharmaceutical engineering, and biotechnology, which are crucial factors in innovation [4].

The limitations of existing therapies, such as drug resistance, poor penetration, and difficulty in tumor targeting, must be overcome [5]. Newer and more effective therapeutic strategies are necessary in the ongoing fight against cancer. Sophisticated mechanisms for drug delivery, diagnostic capabilities, and combined treatments are among the potential solutions provided by nanotechnology to overcome these challenges [6].

Gene mutations cause normal cells to transform into cancer cells (Figure 1). These mutations can be inherited; develop gradually during genetic deterioration with aging; or result from exposure to substances that harm genes, including alcohol, cigarette smoke, or ultraviolet radiation. The behavior of cancer cells differs from that of normal cells. The growth and division of cells become uncontrolled instead of following the normal process of dying. Furthermore, these cells do not mature at expected rates, thus leading to immature state. The many forms of cancer all stem from cells exhibiting abnormal and uncontrolled growth. Cancer has the potential to develop in any cell within the body [7].

Treatment options for cancer, such as chemotherapy, face critical challenges that undermine their effectiveness and patient quality of life. One notable challenge is chemotherapy non-specificity, thus leading to the administration of ineffective drugs targeting both cancerous and normal tissues [8, 9]. This lack of specificity can lead to off-target toxicity and diminished therapeutic efficacy. Drug resistance development in cancer cells is a major challenge in cancer treatment. Cancer cells may develop drug resistance and become unresponsive after initially responding to chemotherapy [8, 10]. This resistance may be caused by decreased drug uptake and increased drug efflux hindering sustained a therapeutic response [11].

Furthermore, chemotherapy can cause several severe adverse effects, including fatigue, anemia, nausea, vomiting, infection, confusion, and depression, which may greatly impact patients’ quality of life [12]. The difficulties in chemotherapy are complex and must be addressed to improve patient outcomes. Increases in targeted treatments and innovative drug administration methods like nanomedicine are crucial for enhancing the efficiency and safety of cancer therapies [9].

The advent of nanotechnology has led to a radical transformation in cancer treatment, allowing for accurate and controlled administration of medicinal substances. LBNPs have attracted substantial interest because of their ability to overcome the limitations of conventional chemotherapy. LBNPs are designed to envelop both hydrophilic and hydrophobic drugs, thereby improving dissolution rates, absorption, and treatment delivery, and consequently minimizing overall toxicity [13, 14]. Several anticancer drugs, such as liposomal doxorubicin, liposomal vincristine, and liposomal paclitaxel, have been delivered via LBNPs and have received clinical approval. These LBNPs provide substantial pharmacokinetic/pharmacodynamic advantages in cancer diagnosis and therapy, such as enhanced therapeutic index and effectiveness, and diminished toxicity [15].

In addition, LBNPs’ superior biocompatibility/biodegradability offer favorable drug solubility and stability in cases of challenging medicine delivery. Furthermore, LBNPs are versatile in improving the therapeutic index through increased efficacy and decreased toxicity, while allowing for chemical changes or surface modifications [16]. These features make LBNPs an attractive strategy for cancer treatment, particularly in combination with other therapeutic modalities. The potential of LBNPs is further enhanced by their ability to cross biological barriers such as the blood-brain barrier, thereby enabling targeted delivery of drugs to specific tissues and organs [17] LBNPs are also helpful in cancer treatment, because they can be used together with methods such as chemotherapy. In addition, nanoparticles have been applied to increase therapeutic efficacy and decrease the adverse effects associated with conventional chemotherapy. These characteristics render LBNPs potentially helpful in managing cancer alongside other treatment options.

LBNPs enhance the bioavailability and solubility of hydrophobic compounds, thereby improving the precision of targeting of cancerous cells and resulting in more effective drug delivery. Injection of LBNPs directly into tumors enhances the local concentration of chemotherapeutic agents while minimizing systemic exposure [18]. Additionally, LBNPs enhance the sensitivity of cancer cells to chemotherapy, radiotherapy, and immunotherapy, by overcoming drug resistance mechanisms, such as decreased drug uptake and increased efflux. Consequently, the controlled release of drugs in response to specific stimuli in the tumor microenvironment leads to improved therapeutic outcomes [17].

The emergence of nanotechnology has greatly facilitated the development of LBNPs with potential to improve cancer diagnosis and treatment. Their unique properties and capabilities make them an attractive strategy for enhancing therapeutic efficacy and decreasing the toxicity of anticancer drugs.

This article comprehensively explores LBNPs for cancer treatment. The objectives of this review are as follows:

• Describe the limitations of traditional chemotherapy, such as non-specificity, severe adverse effects, and drug resistance, and underscore the need to develop new-generation targeted therapies
• Explore how nanotechnology is used to treat cancer, with specific reference to LBNPs, which significantly increase the effectiveness and safety of anticancer drugs
• Discuss types of LBNPs, according to their biocompatibility, ability to encase hydrophilic and hydrophobic drugs, and biodegradability, which enable enhanced therapeutic efficacy while decreasing toxicity
• Highlight applications of LBNPs in cancer treatment, including their use in combination therapy, and discuss recent advances in LBNP technology, such as synthesis methods using novel surface coatings
• Provide a comprehensive summary of the current status of LBNPs in cancer therapy, including prospects, challenges, and future directions, to guide the design of better-oriented anti-cancer treatments

The article is organized as follows. Section 2 describes the characterization of LBNPs; Section 3 discusses the classification LBNPs; Section 4 provides a summary of LBNP synthesis; Section 5 emphasizes strategies for targeting cancer cells with LBNPs; Section 6 describes data from current clinical trials; Section 7 discusses challenges and future perspectives; and Section 8 presents conclusions regarding LBNPs, a new generation of drug delivery systems with promise for cancer therapy, conferring major advantages over conventional chemotherapeutic approaches.

Characterization of LBNPs

Morphology of LBNPs

The morphology of LBNPs is a crucial characteristic affecting their interactions with biological systems, including cellular uptake and in vivo stability. The dimensions and shapes of LBNPs can be evaluated with techniques such as dynamic light scattering (DLS), transmission electron microscopy (TEM), and small angle neutron scattering [19, 20].

Many studies have demonstrated that the morphology of LBNPs significantly affects their cellular uptake. For instance, nanodiscs demonstrate higher cellular uptake than nanovesicles, even if they have the same lipid composition; consequently, nanodiscs’ distinctive morphology might facilitate greater cellular internalization [21].

A key to optimizing LBNP design and formulations for specific therapeutic applications in nanomedicine is a proper understanding of the morphology of LBNPs. Controlling factors such as lipid composition, synthesis technique, and surface modifications may alter the morphology of LBNPs [22]. To date, the morphological behavior of lipid nanoparticles has been investigated with cryogenic transmission electron microscopy (Cryo-TEM). Zhigaltsev et al. (2023) have found that changing the composition of lipids markedly alters the morphology of LBNPs. We have discovered that multilamellar structures are found under certain conditions when cone-shaped lipids such as dioleoyl-sn-glycero-3-phosphoethanolamine are included. In contrast, a standard lipid mixture and distilled water yield unilamellar vesicles. This morphological flexibility has enabled optimization of LBNP systems for specific drug delivery applications [23].

Shape and size distribution

LBNPs’ stability and circulatory endurance depend on their shape, size distribution, and cellular uptake. These characteristics have been addressed with various synthesis techniques and formulation approaches [24].

The size and distribution of LBNPs in liposomes or other systems can be measured with light scattering techniques such as DLS, static light scattering, or nanoparticle tracking analysis. Another important technique for studying LBNP morphology and sizing is Cryo-TEM [25, 26].

A uniform and accurate size distribution is necessary for achieving optimal clinical outcomes with LBNPs. Because nanoscale systems have much larger specific surface areas than microsystems, particular attention must be paid to any changes in size during the production of encapsulated therapeutic agents. [24, 27].

Liposomes range in size from 50 to 500 nm, and have spherical, unilamellar, or multilamellar shapes [23]. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) generally have diameters of 100–300 nm, and predominantly elliptical or spherical geometry [28].

DLS remains a standard technique to assess LBNP size distribution. A recent article in Nature has highlighted a novel approach to quantitatively characterizing the size-resolved properties of lipid nanoparticles. DLS, hydrodynamic diameter, and the polydispersity index were used to analyze several formulations, and small particles (≤100 nm) were found to yield favorable encapsulation efficiency and stability. In particular, this finding highlights the role of precise size control in improving therapeutic efficacy [29].

Surface charge

The interactions of biological systems with LBNPs are greatly affected by LBNP surface charge, which determines stability, circulation, and cellular uptake. Positive, negative, or neutral surface charges are chosen in LBNP design, depending on the application and the target tissue [30].

Lipids with charged head groups can also be incorporated into dioleoyl phosphatidylserine:dioleoyl-sn-glycero-3-phosphoethanolamine liposomes or cationic lipids to modulate surface charge. Surface charge selection depends on several factors, such as the drug type, specific cell populations or tissues that must be reached, and intended pharmacokinetic profile [31].

The stability and interaction of LBNPs with biological systems depend on their surface charge. High-field nuclear magnetic resonance spectroscopy has been applied to elucidate lipid composition at the mRNA-LNP surface. The surface charge and stability of mRNA-LNPs strongly depend on the presence of polyethylene glycol (PEG) chains, which improve circulation time and cellular uptake. Studies have been aimed at understanding the role of surface modification in maximizing the performance of LBNP for drug delivery [32, 33].

Phase transition temperature

The transition temperature, the temperature at which the lipid bilayer undergoes conformational changes from a gel to liquid crystalline phase, is a crucial parameter affecting the stability and performance of LBNPs [20].

Nano-plasmonic sensing (NPS) is a technique for accurately determining the T_m of phospholipids by detecting conformational changes in liposomes during the phase transition. Knowing T_m is essential for optimizing the stability and performance of LBNPs, because it affects drug release kinetics and in vivo behavior [20].

Knowledge of the thermal stability and behavior of lipid formulations requires the determination of phase transition temperatures (T_m). Recently, NPS has been demonstrated to be a novel method for determining the T_m values of phospholipids. We have found that NPS accurately identifies T_m transitions and is comparable to traditional differential scanning calorimetry methods. This finding provides a straightforward process for the determination of lipid phase behavior that is critical for the development of stable LBNP formulations [20].

Protein-plasma interaction, clearance, and particle stability

In vivo, LBNPs react with various plasma proteins and consequently influence their stability, persistence, and excretion from the body. Understanding these interactions is crucial for the rational design of LBNPs with improved therapeutic efficacy [18].

For example, protein corona formation is influenced by size, surface charge, and surface modifications, thus leading to subsequent changes in LBNP behavior in vivo. PEGylation of LBNPs, for instance, minimizes protein adsorption and hence increases their persistence within the circulation [34].

Regulating the stability of LBNPs during storage is also essential to maintain quality, safety, and efficacy. For example, ionic strength, pH, and temperature influence the stability of LBNPs, and specific conditions must be established for each formulation [21].

In conclusion, it is essential to study the properties of substances to understand and improve their efficiency when used as medicine. Important factors to consider include size, surface charge, morphology (shape), phase transition temperature (melting point), plasma protein interaction, and other relevant characteristics. This comprehensive approach is crucial for developing successful drug delivery systems.

Understanding how LBNPs interact with plasma proteins is essential for predicting their behavior in vivo. A pharmaceutical research study has examined the adsorption of serum proteins onto lipid nanoparticles with advanced analytical techniques. Specific surface modifications were found to decrease protein adsorption, thereby potentially minimizing opsonization and enhancing circulation time. This insight is critical for improving the pharmacokinetics of LBNPs in therapeutic applications.

Stability studies are fundamental for ensuring the efficacy of LBNPs over time. Recent research has focused on evaluating the stability of SLNs under various storage conditions with DLS and zeta potential measurements. These studies have revealed that SLNs maintain their size and charge over extended periods when stored under optimal conditions, thus highlighting their potential as stable drug delivery systems.

The clearance mechanisms of LBNPs from biological systems significantly influence their therapeutic efficacy. Recent studies have used advanced imaging techniques to track lipid nanoparticle biodistribution and clearance pathways in vivo. These investigations have provided insights into how modifications to nanoparticle size and surface properties can influence their pharmacokinetics and overall therapeutic effectiveness [30].

Classification of LBNPs

LBNPs have emerged as promising drug-delivery structures for most cancer treatments [18]. These nanoparticles are composed of lipids, which can encapsulate both hydrophilic and hydrophobic therapeutic agents, thus enhancing their solubility, bioavailability, and targeted delivery to tumor sites [35]. Several drug delivery properties of LBNPs and their classification are described in Figure 1.

The classification of LBNPs is shown in Figure 2. The state and composition of LBNPs’ lipid components significantly influence the particles’ physicochemical properties, drug release kinetics, and drug loading capacity [36]. Understanding the different types of LBNPs and their unique characteristics is crucial for selecting appropriate formulations for specific cancer therapies. LBNPs are the most common category of nanomedicines with Food and Drug Administration-approved nanocarriers (Table 2).

Liposomes

Liposomes, the most well-known and studied LBNP type, are round vesicles composed of a phospholipid bilayer encapsulating an aqueous core [27]. The phospholipids used in liposomes, along with phosphatidylcholine (PC) and phosphatidylethanolamine, have an amphiphilic structure with a hydrophilic head group and a hydrophobic tail [37].

The self-assembly of these amphiphilic lipids drives the formation of liposomes in aqueous environments [38]. When the lipids are dispersed in water, their hydrophobic tails aggregate, thereby minimizing their contact with the aqueous phase, while the hydrophilic head groups interact with the surrounding water molecules [39, 40]. This process spontaneously forms a closed bilayer structure known as a liposome.

Liposomes can be designed to contain a wide range of hydrophilic and hydrophobic therapeutics in their pores and lipid bilayers, respectively [41]. This versatility makes liposomes a platform of interest for delivery of a variety of drugs, such as small molecules, proteins, nucleic acids, and imaging agents [42]. Liposome surface charge, size, and lipid composition can be tailored to optimize their pharmacokinetic and biodistribution properties [43]. For example, incorporation of cholesterol can enhance the stability of the lipid bilayer. Simultaneously, the introduction of PEG extends the circulation time of liposomes by decreasing their detection and clearance by the reticuloendothelial system [44].

Liposomes’ multiple advantages make them a promising drug delivery system for cancer treatment (Table 1). Liposome formulations such as liposomal doxorubicin (Doxil/Caelyx) and liposomal vincristine (Marqibo) have been accepted for clinical use in the treatment of various types of cancer [57]. Overall, liposomes’ unique properties and versatility have made them a widely explored and successful class of LBNPs for cancer nanomedicine.

Solid lipid nanoparticles

SLNs are promising drug delivery systems that use solid lipids as the carrier matrix. SLNs offer various advantages for the delivery of hydrophobic drugs and controlled drug release [58]. A primary advantage of SLNs is their ability to encapsulate and deliver hydrophobic drugs effectively (Table 1). The solid lipid matrix provides a suitable environment for the incorporation of lipophilic drugs, thereby enhancing their solubility and bioavailability [59, 60]. The incorporation of hydrophobic drugs into the solid lipid matrix protects them against degradation and premature release, and ensures their stability during storage and delivery [58, 61]. Additionally, the large surface area and small size of SLNs contribute to improved drug solubility and absorption, thus further increasing the bioavailability of hydrophobic drugs [62].

SLNs also offer an advantage of controlled drug release, which is particularly beneficial for maintaining therapeutic drug concentrations and decreasing administration frequency [63]. The solid lipid matrix acts as a barrier slowing the diffusion of the encapsulated drug and providing a sustained release profile [64]. The release kinetics of drugs from SLNs can be tailored by modifying the lipid composition, drug loading, and surface properties of the nanoparticles [62]. For example, the incorporation of specific lipids or the addition of polymeric coatings can further control the drug release rate and target specific tissues or cells [65].

NLCs can encapsulate a variety of therapeutic agents, including hydrophilic and hydrophobic drugs, as well as proteins and peptides. Moreover, NLCs can be surface modified to bear targeting ligands that improve their specificity and accumulation at desired sites of action, e.g., tumor tissues [58, 66]. Furthermore, the small size and high surface area of SLNs allow for efficient cellular uptake and tissue penetration, thereby enabling targeted drug delivery to specific sites of action [67, 68]. The net effects may include increased drug accumulation at target sites and decreased systemic toxicity. Because solid lipid nanoparticles offer a favorable platform for delivering hydrophobic drugs, and confer advantages of improved solubility, increased bioavailability, and potentially controlled drug release, their use in ophthalmic delivery should be further developed. These particles’ small size and high surface area also enhance drug dissolution and absorption, and the solid lipid matrix protects encapsulated drugs against degradation and premature release [69]. By tailoring the lipid composition and surface properties, the release kinetics of drugs from SLNs can be optimized for specific applications, thus increasing therapeutic efficacy and decreasing adverse effects [70].

Nanostructured lipid carriers

NLCs are second-generation LBNP systems developed as an alternative to first-generation SLNs. NLCs are designed to overcome the limitations of SLNs while retaining their advantages and combining the beneficial properties of liposomes (Table 1) [70].

SLNs were initially developed to address challenges with conventional lipid-based drug delivery systems, such as emulsions and liposomes. However, SLNs have several inherent limitations. For example, the rigid structure of the solid lipid matrix in SLNs can lead to drug expulsion during storage, particularly for drugs with high solubility in the lipid phase [71]. Moreover, the lipids used in SLNs can undergo polymorphic transitions during storage, thereby affecting the system’s physical stability and drug encapsulation efficiency. Finally, the highly ordered structure of the solid lipid matrix in SLNs can limit the amount of drug that can be incorporated, thus leading to relatively low drug loading capacity [62].

NLCs were developed to overcome the constraints of SLNs. Unlike SLNs, NLCs comprise both solid and liquid lipids, which result in a less ordered and more deformable lipid matrix. This unique structure allows liquid lipids in the NLC matrix to create more space for drug molecules, thereby enabling a higher drug-loading capacity compared to SLNs [72]. The less ordered structure of the NLC matrix, compared to the more ordered structure of SLNs, makes it less susceptible to drug expulsion during storage. This results in improved physical and chemical stability of the formulations. NLCs can be formulated with biocompatible and biodegradable lipids, thereby decreasing the potential for cytotoxicity and improving the safety profile [73]. NLCs can be designed to deliver a wide range of therapeutic agents—including hydrophilic and hydrophobic drugs, proteins, and peptides—and are readily surface-modified with targeting ligands to improve the specificity and accumulation of the vehicles at sites of action, such as tumor tissues [72, 74]. NLCs combine the advantages of both SLNs and liposomes and therefore provide a versatile and promising drug delivery platform. The solid lipid matrix of NLCs enables physical stability and controlled drug release, whereas the incorporation of liquid lipids increases the drug loading capacity and prevents drug expulsion during storage [28, 75]. Additionally, the lipid composition of NLCs can be tailored to mimic the structures and properties of liposomes, thus allowing for loading with both hydrophilic and hydrophobic drugs. The unique design of NLCs enables them to overcome the limitations of conventional lipid-based delivery systems, and makes them a valuable tool for developing advanced drug delivery strategies, particularly for cancer therapeutics and other challenging drug candidates [30].

Lipid-polymer hybrid nanoparticles

Lipid-polymer hybrid nanoparticles (LPHNPs) represent an emerging drug delivery system. They consist of two major components: a polymer core and one or more lipid layers forming an outer shell [52]. Structurally, LPHNPs, like solid lipid nanoparticles, are solid at body temperature. However, they are distinct from generally used lipid-based nanocarriers such as liposomes, which have a hydrophilic core enclosed by a lipid-PEG layer. Various targeting agents, such as folic acid, arginyl glycyl aspartic acid, or antibodies, can also be attached to the lipid-PEG layer to achieve targeted delivery [76]. In LPHNPs, the drug can be either hydrophilic or hydrophobic and is encapsulated by the polymer core (inner portion). The external side of the polymer core is surrounded by the lipid shell (outer layer), which prevents rapid diffusion of the drug and enables sustained drug release [51].

The lipid and polymer can have therapeutic agents entrapped, adsorbed, or covalently attached. The LPHNP system improves drug uptake and intracellular drug transport, boosts drug loading efficiency, enables regulated drug release, and helps drugs overcome membrane efflux transporter-mediated multidrug resistance in cancer cells [51, 76]. However, despite these benefits, polymeric nanoparticles are characterized by toxic degradation, monomer accumulation, and a harmful degradation mechanism, which limits their use as nanomaterials. Other drawbacks of lipid nanoparticles include the potential instability of lipid nanoparticles (e.g., because of drug ejection or gelation) during storage and administration, low drug loading capacity, low membrane retention, decreased cell membrane fluidity, and unstable physical states of lipids [77].

LPHNPs evolved as a solution to the restrictions of both lipid LBNPs and polymeric LBNPs. These LBNPs are known as “hybrids,” because they combine the traits of lipid and polymeric particles. Drug release is regulated by the polymer, and drug loading and penetration across the membrane are enhanced by the lipid [78]. Intracellular drug targeting is achieved by particles smaller than 100 nm; numerous hydrophilic and hydrophobic therapeutic agents are concurrently delivered and entrapped by the LPHNPs. LPHNPs also enable targeted drug delivery due to their adjustable surface charge. They offer excellent scalability, physical stability, and biocompatibility [79]. The nanoparticles have low cytotoxicity and favorable biocompatibility, and consequently are suitable for biomedical applications. Lipid-polymer hybrid nanoparticles, which combine the stability and protection of lipids with the controlled release and improved circulatory properties of polymers, have intriguing potential as innovative therapeutic vehicles for drug administration [80].

Other LBNP types

Phytosomes

Phytosomes are a novel lipid-based delivery method structurally resembling liposomes. “Phyto” refers to plants, whereas “some” refers to cells. Phytosomes are also known as herbosomes. In this unique technique for drug delivery, phospholipids enclose and bind biologically active phytoconstituents of plant extracts [53]. Phytosomes can be used to entrap various phytoconstituents based on polyphenols and enhance their absorption after administration [81]. The first phytosomes were developed by the Indena firm (Milan, Italy) in the late 1980s to formulate complex medications for phospholipids to enhance their bioavailability. The structure of phytosomes comprises phytochemical complexes, which were developed by incorporating standardized polyphenolic plant extracts into phospholipids, primarily PC [82]. Phytosomes are lipid vesicles formed by the action of the phosphate group of the phospholipid matrix in non-polar solvents on the polyphenolic moiety of bioactive herbal extracts through H-bonding [83]. The phytosome body is formed through the high tendency of flavonoids and terpenoids, two types of phytochemicals with water-soluble polyphenolic rings, to chemically bind the hydrophilic moiety of phospholipids (choline) [53, 81]. Herbal extracts in phytosomes have been complexed with phospholipids to increase the medicinal effects of herbal supplements and conventional medications by facilitating absorption and bioavailability. By forming molecular complexes with phospholipids, typically PC, phytosomes enhance the solubility of poorly water-soluble phytoconstituents [84].

Phytosomes have been used to increase the bioavailability of antioxidants, vitamins, and herbal extracts, thereby enhancing their efficacy in various applications related to health and well-being. LBNPs and phytosomes are cutting-edge drug delivery technologies aimed at increasing the effectiveness of pharmaceutical and nutraceutical chemicals by addressing low drug solubility, stability, and bioavailability problems [85]. The distribution of ginkgo herbal extract with phytosome nanotechnology has been found to elicit positive effects on the pharmacokinetic profile, and protection of the brain and blood vessels [86].

Specific essential liposome properties are retained by phytosomes, such as the ability to make poorly soluble compounds, including polyphenolic phytochemicals, more soluble [87]. Phytosomes are nanopreparations used to distribute hydrophilic ingredients with low absorption and bioavailability, because the constituents’ diffusion through lipid membranes is retarded by their large molecular size or extremely poor lipid solubility. Phytosomes are made up of phospholipids, which chemically bind loaded chemicals and form complexes. Because they are miscible in lipids and water, phytosomes have high oral bioavailability [88].

PC and active substances can be complexed at specified molar ratios to create phytophospholipid complexes. PC is a bifunctional molecule, with the choline fraction being hydrophilic and the phosphatidyl fraction being hydrophobic. The photosensitive component of the phytophospholipid complex is attached to the choline lead surrounding the PC speck and is surrounded by the lipid-soluble portion, thus creating a phytophospholipid complex [89].

Lipid Coated Nanoparticles

Lipid-coated nanoparticles are a valuable class of drug delivery systems comprising small particles encased in a layer of lipid or fat to enhance medication delivery to certain anatomical sites. To achieve high biocompatibility and drug loading capacity, combining the benefits of the two main drug nanocarrier system classes, polymeric nanoparticles and liposomes, is advantageous [90]. Various lipid molecules can be introduced on the nanoparticle surface and subsequently aggregate with hydrophobic or amphiphilic medicines, or active molecules, for cell targeting. Naturally occurring biological membranes and lipid components provide the essential structural framework [91]. Phospholipids make up most cell membranes, which serve as a barrier shielding cell components from the extracellular environment [92]. A typical LBNP consists of a lipid coating for biocompatibility and a polymeric core encasing the payload to be delivered. The lipid shell might have two layers, one on top of the other [93]. Coating the nanoparticle surface is essential to ensure nanoparticles’ colloidal stability in aqueous solution, improved biocompatibility, and particular cell targeting functions [94, 95].

Lipid-coated nanoparticles enhance drug effectiveness while decreasing toxicity. They are used to target drugs to specific regions of the body. These nanoparticles can be conjugated with contrast or fluorescent dyes for magnetic resonance imaging, computed tomography, optical imaging, and many other applications. Together with biosensing and biomarker detection, lipid-coated nanoparticles are applied for a variety of diagnostic purposes [96].

In general, lipid-coated nanoparticles are a highly favorable drug carrier approach, because these particles are biocompatible, and can be tuned for specific applications and enhance the pharmacokinetics of delivered drugs. These nanoparticles are at the frontier of research on various medical applications, such as cancer treatment, drug delivery, and targeted approaches to medicine. To achieve nanoparticle colloidal stability in aqueous solution, enhancing biocompatibility, and unique cell targeting functionalities, the nanoparticle surface must be coated [95].

LBNP synthesis

LBNPs can be prepared through various techniques, including those used to prepare SLNs and NLCs. This section describes techniques frequently used to synthesize LBNPs (Figure 3). Several criteria are additionally proposed for selecting the optimal approach for a given class of LBNPs, and benefits and drawbacks are considered.

Bulk nanoprecipitation

The solvent displacement, or bulk nanoprecipitation, technique was first invented and patented by Fessi et al. in 1989 to produce nanoparticles [97]. An aqueous phase is mixed with a water-miscible solvent containing lipids and hydrophobic drugs, known as the organic phase, to cause supersaturation, which in turn leads to the nucleation and subsequent development of nanoparticles [62]. The hydrophobic payloads, polymer, and lipid must typically be dissolved in an aqueous phase and added with a water-miscible organic solvent in a conventional nanoprecipitation procedure. Through hydrophobic interactions, the lipids self-assemble onto the polymer nanoparticles when the polymer is added dropwise while the mixture is continuously stirred [51]. LBNPs are formed and stabilized when the lipids’ hydrophilic heads are attached to the external aqueous environment, and the lipids’ hydrophobic tails are joined to the polymer core.

After particle production, dialysis, ultracentrifugation, rotary evaporation, and freeze-drying may be used to extract the organic solvent from the formulation [98].

The technology of nanoprecipitation, which produces specified nanoparticles without a need for additives, is simple, low in energy consumption, and broadly applicable. To prevent aggregation and increase nanoparticle stability during the process, a stabilizer must be present [99]. However, the primary disadvantage of bulk nanoprecipitation is that the restrained control of fluidic dynamics results in nanoparticles with a broad length distribution, particularly with large blending volumes and large-scale manufacturing. Additionally, incomplete mixing can lead to variations in nanoparticle properties from batch to batch, making it unsuitable for large-scale manufacturing [30]. To decrease nanoparticle length, the mixing time must be less than the characteristic precipitation time, i.e., mixing must be completed before precipitation occurs.

This method is frequently used to obtain nanoparticles with precise size, shape, and composition requirements for a wide range of uses in industries such as materials science, electronics, and medicine [100].

Coacervation method

A novel solvent-free method for making lipid nanoparticles for medication distribution is called coacervation. One polymer serves as the primary polymer forming nanoparticles, whereas the other serves as a coating material. Both polymers are dissolved in a solvent [101]. In 1997, the separation of colloidal systems into two liquid phases was described as coacervation by the International Union of Pure and Applied Chemistry. This process involves the passive movement of colloidal systems into distinct phases without any external intervention [102].

The generation of nanoparticles occurs through phase separation of the primary polymer in the solution when specific conditions are met, such as variations in pH, temperature, or the addition of electrolytes [103]. The coating material subsequently creates a shell around these nanoparticles that provides stability and controlled medication release. This method involves raising the temperature of aqueous solutions containing a particular salt of fatty acids above their Krafft point, the temperature above which a surfactant’s solubility equals the critical micellar concentration. In this process, heating the lipid solution is essential. Subsequently, the stabilizer solution and a coacervating agent are added to the emulsion to initiate the creation of LBNP through a pH shift [101, 104]. The mixture is subsequently promptly chilled under constant stirring. Differential scanning calorimetry has indicated that the medicine retrieved from the nanoparticles is crystalline, and spherical nanoparticles are produced. Three main drug distributions within lipid nanoparticles have been described: a homogeneous matrix, a shell layer containing drugs at a higher concentration than that in the core, and a central core containing medications at higher concentration than that in the shell layer [105]. The coating technique involves the formation of three immiscible chemical layers. First, the liquid portion of the coating material is separated from the polymeric solution. It is then uniformly coated as a layer across the suspended core particles. Finally, the coating is solidified [106].

Phase separation results from the coacervation process, which decreases the protein’s solubility. When a desolvating chemical is added, the protein’s structure undergoes conformational changes that cause coacervation or precipitation. The size of nanoparticles in the coacervate can be regulated by adjustment of processing variables. Agents such as glutaraldehyde and glyoxal are used to cross-link nanoparticles after they have been produced [101, 107]. The coacervation process is a favorable method for creating nearly monodisperse nanoparticles for medication delivery [105]. This method is simple but can be applied only to lipids such as fatty acids that can generate alkaline salts.

Non-solvent emulsification

Emulsion formation without solvent use is a non-solvent or melting emulsification technique. In this method, water-insoluble substrates are used as the liquid phase to prepare oil-in-water emulsions, instead of using solvents to dissolve lipids. This method generally entails transformation of solid lipids into liquids at temperatures slightly above their melting points, in a range of 5–10°C [108]. After melting, the lipids are emulsified with an aqueous phase containing surfactants through membrane emulsification, high-pressure homogenization, high-speed stirring, microemulsions, and ultrasonication to form nanoemulsions [109]. These dispersed SLNs can be prepared by allowing the nanoemulsions to crystallize in an ice bucket [108]. The duration of the sonication process, length of homogenization, concentrations of medicines, concentrations of lipids, lipid type, and surfactant type are several variables affecting the LBNP production and characteristics [110]. The solubility of medications in lipids affects their drug-loading capacity. Therefore, the surfactant should ideally have an hydrophilic-lipophilic balance value between 12 and 16. Smaller particle sizes have been identified with increases in sonication times and surfactant concentrations [111]. Nonsolvent-based emulsification methods decrease toxic solvent effects on LBNP solutions, because no toxic organic solvents are used [97].

Non-solvent emulsification is an easy, rapid, and widely used technique for producing stable emulsions without requiring additional solvents, in industries including food, medicine, and cosmetics. This method is also applied to produce drug-delivery nanoparticles with regulated drug release characteristics and a limited size distribution [112].

Microfluidic approaches

Microfluidic approaches: In microfluidics, a useful technique for creating nanoparticles, small amounts of fluids are precisely controlled within microchannels in microfluidic devices. This method allows for the creation of nanoparticles with specific sizes, shapes, and characteristics [113]. The precise manipulation and control of fluids at the microscale level are enabled by the powerful technology of microfluidics. A large variety of nanoparticle materials can be produced through microfluidic technologies. Typical applications of microfluidics include the production of organic nanoparticles, such as liposomes, lipids, or polymers [114, 115]. Nanoprecipitation serves as the basis for the synthesis of organic nanoparticles. To create consistent organic nanoparticles with adjustable and regulated characteristics, microfluidics is an ideal method [116].

Microfluidic devices are extensively used in nanotechnology and are designed to manipulate fluids in channels at the microscale. Devices can create LBNPs through a microfluidic device in two broad categories, chip-based and capillary-based, through hydrodynamic flow focusing [117]. In microfluidic systems, nanoparticle synthesis is performed in microreactors, which typically have inner diameters less than 1 millimeter. This method combines two immiscible liquids (water and oil) in a microfluidic device to form an emulsion, which serves as a model for the production of nanoparticles [118]. Nanoparticles can be formed by initiation of chemical reactions or precipitation processes within the emulsion droplets. The size and content of the nanoparticles can be precisely customized by adjusting the flow rates and mixing conditions in the microfluidic device. The nanoparticles can be removed from the microfluidic device downstream for additional processing or examination after being produced [119].

Microfluidic techniques apply to various nanoparticle tasks, such as production, functionalization, and characterization. For example, the design of microfluidic devices facilitates the controlled combination of chemicals at the microscale level to produce homogeneous nanoparticles with desired properties [120].

Solvent-based emulsification

Solvent-based emulsification is preferred for potentially hydrophobic drugs soluble in water-insoluble organic solvents. In this method, polymers are dissolved in an organic solvent, the active drug is dissolved or dispersed in the same medium, and the oil organic phase is emulsified in an aqueous solution containing a suitable emulsifying agent [121]. The active ingredient must have low solubility in the continuous phase. The emulsion is separated from the volatile solvent by evaporation, extraction to a constant phase, or both methods. The continuous phase must be immiscible with the oily dispersed phase [122].

This process produces oil-in-water emulsions by dissolving lipids and poorly water-soluble medications in an organic solvent and emulsifying them with an aqueous solution. Centrifugation is used after the emulsion evaporates under stirring to extract the organic solvent. When the solvent evaporates, the lipid molecules are in proximity as the interfacial tension between the lipid and aqueous phases decreases [64]. Throughout the emulsification process, many parameters can be adjusted to control the size and stability of the nanoparticles. Pharmaceuticals sensitive to temperature can be encapsulated with this method [65, 123]. The solvent emulsification-evaporation approach is used to generate SLNs and NLCs. Thus, drugs and lipids are dissolved in a solvent or a mixture of solvents and then emulsified in an aqueous phase [124]. The organic solvent is then removed with a rotary evaporator or mechanical stirring. Lipid precipitation after solvent evaporation results in the formation of SLNs and NLCs [125].

In conclusion, solvent-based emulsification is a flexible method for creating LBNPs that can be used to efficiently encapsulate medications, regulate particle size, and optimize formulation parameters for precise and efficient drug delivery [126].

Supercritical fluid technology

Nanoparticle preparation is accomplished with the supercritical fluid (SCF) approach. SCFs are used in this technique as solvents to dissolve and precipitate the nanoparticles [127]. A material that has both gas and liquid characteristics, because it is above its critical temperature and pressure, is known as an SCF. The essential components are dissolved in the SCF, after which the process proceeds with rapid growth or depressurization, thus causing the nanoparticles to precipitate [128]. A notable feature of this technique is the absence of organic solvent use during the fabrication of nanoparticles. This technique can also yield high-purity nanoparticles with homogeneous drug distribution. In this method, polymers and drugs are dissolved in the SCF, and the solution expands through a narrow orifice. Relatively lower solvent power leads to the coagulation of the solute into solvent-free nanoparticles [129]. This method is suitable for only low-molecular-weight polymers. The technique cannot be easily applied to produce a wide range of nanoparticles, because most polymers are not soluble in SCFs. SCF technology is a technique used in the formulation of various nanoparticles with the aid of supercritical CO₂ and H₂O [130]. Carbon dioxide is the most widely used SCF, because of its exceptional safety and reasonable cost. The most frequently used technique using SCF to produce LBNPs involves changing the supercritical CO₂ (scCO₂) ambient pressure. In summary, scCO₂ is used as a solvent, and solid lipids and pharmaceuticals become more soluble in scCO₂ when fed into a high-pressure tube. The medications and solid lipids then rapidly become supersaturated and precipitate. Drug-loaded LBNPs are subsequently produced through the depressurization procedure, which causes the solid lipids and medications to become supersaturated and rapidly precipitate [128, 131].

This technique has advantages of yielding high-purity nanoparticles and allowing for maintenance of the size and morphology of the particles. It is frequently used in many industries, including nanotechnology, materials science, and medicines. The ability to alter the physical properties of supercritical fluids (SCFs) by manipulating temperature and pressure is considered a critical advantage of SCFs. This unique characteristic allows for various industrial applications, including pharmaceuticals, food processing, and environmental remediation [132]. Drugs can be encapsulated within nanoparticles with this technology, thereby improving their solubility, stability, and targeted distribution to particular human regions or cells, and aiding in drug delivery applications. The technique of coating solid dosage forms and liposome formulations and decreasing particle size is applied in the pharmaceutical industry [130, 133].

Strategies for targeting cancer cells with LBNPs

Passive targeting

Passive targeting leverages the unique properties of cancer cells to deliver therapeutic agents by nanocarriers [134]. This process involves the passive diffusion or convection of medications into the tumor mesenchyme or cells through the gaps in tumor capillary walls [135]. Convection, the movement of molecules within a fluid, is the primary method for transporting macromolecules when the net filtration rate is zero. Simultaneously, low-molecular-weight substances such as oxygen are transferred primarily by diffusion. Driven by, a concentration gradient, diffusion becomes the primary drug delivery mechanism, because the high tumor interstitial pressure restricts convection. Tumor blood vessels exhibit elevated capillary permeability, thus leading to nanoparticle aggregation within the tumor because of inadequate lymphatic drainage [136, 137]. The enhanced permeability and retention (EPR) effect, characterized by a hyper-permeable tumor vasculature and impaired lymphatic drainage, facilitates the accumulation of nanoparticles in the tumor microenvironment. This passive targeting is influenced by the intrinsic properties of nanoparticles, such as their size, shape, and surface charge, and the unique features of the tumor microvasculature, which have larger pore diameters than normal capillaries. Consequently, liposomes can passively target tumor tissues effectively [136, 138].

LBNPs exploit the EPR effect for passive targeting in cancer therapy. In healthy tissues, the tight junctions of epithelial cells and efficient lymphatic drainage prevent nanoparticles from accumulating [16]. However, in tumor tissues, the defective vasculature with gaps between endothelial cells and impaired lymphatic drainage allows nanoparticles to exit the bloodstream and accumulate within tumors [139]. This selective accumulation occurs because of the leaky vasculature and poor lymphatic clearance in tumors, and enables LBNPs to deliver therapeutic agents directly to cancer cells, thereby enhancing treatment efficacy while minimizing damage to healthy tissues (Figure 4) [16, 140].

By exploiting the EPR effect, LBNPs achieve selective accumulation in tumor tissues. This mechanism has been highlighted in studies demonstrating that PEGylated liposomal doxorubicin (Doxil) achieves higher tumor concentrations than free doxorubicin and consequently decreases systemic adverse effects [141].

Active targeting

Active targeting strategies have been extensively used to enhance nanoparticle drug delivery. This approach involves modifying nanoparticles with specific ligands, antibodies, or other molecules that bind receptors on target cells, thereby increasing cellular absorption and therapeutic efficacy [142]. These ligands, which include nucleic acids, peptides, proteins, polysaccharides, and small molecules, enable precise medication delivery and decrease cytotoxicity and adverse effects on healthy cells. Nanoparticles can form through physical adsorption, chemical conjugation, or coupling with nanoparticle constituents such as polymers [143]. In tumor targeting, active targeting is activated after the drug has passively accumulated in the tumor area, thus enhancing its effectiveness against cancer cells. This is achieved by binding ligands to receptors overexpressed on tumor cells, thereby increasing drug diffusion and nanoparticle affinity for cancer cells [144]. The goal is to deliver therapeutic drugs specifically to cancer cells while sparing healthy cells by using ligands that are recognized by receptors on cancerous cells, ensuring targeted drug delivery [139, 145].

The active targeting of cancer stem cells with LBNPs is shown in Figure 5, which indicates three types of cells: a generic nanoparticle, a cancer stem cell, and a differentiated tumor cell [146]. Cancer stem cells with specific surface markers are the targets of the nanoparticle’s targeting moiety. This moiety, responsible for the nanoparticle’s ability to bind cancer stem cells, is connected to the nanoparticle via a linker chain. The nanoparticle in turn carries chemotherapeutic agents [147]. This setup allows the nanoparticles to bind cancer stem cells selectively, thereby ensuring precise delivery of chemotherapy drugs to the cancer cells while sparing healthy cells. This strategy significantly enhances the effectiveness of cancer treatment by focusing on the unique markers present in cancer stem cells [148].

Folate-conjugated lipid nanoparticles have demonstrated significantly enhanced cellular uptake and cytotoxicity against folate receptor-positive cancer cells, and have outperformed non-targeted formulations. Ligand-based targeting strategies have been demonstrated to improve drug delivery to specific tumor cells. In addition, docetaxel-loaded nanoemulsions labeled with gadolinium have a size distribution of approximately 150 nm with a zeta potential of approximately −45 mV. The active targeting of folic acid significantly enhances cell association, in a manner dependent on the surface ligand density [149].

Active targeting strategies have been extensively used to enhance nanoparticle drug delivery. This approach involves modifying nanoparticles with specific ligands, antibodies, or other molecules that bind receptors on target cells, thereby increasing cellular absorption and therapeutic efficacy [133]. These ligands, which include nucleic acids, peptides, proteins, polysaccharides, and small molecules, enable precise medication delivery, and decrease cytotoxicity and adverse effects on healthy cells. In tumor targeting, active targeting is activated after the drug has passively accumulated in the tumor area, thus enhancing effectiveness against cancer cells. This is done by binding ligands to receptors that are overexpressed on tumor cells, increasing drug diffusion and nanoparticle affinity for cancer cells. The goal is to deliver therapeutic drugs specifically to cancer cells while sparing healthy cells, by using ligands that recognize and bind markers on cancerous cells [149, 150].

Stimulus-responsive LBNPs

Nanotechnology-based drug delivery systems offer substantial benefits in treating, diagnosing, and preventing various diseases. Stimulus-responsive strategies involve developing substances or therapies that react to specific stimuli in the tumor microenvironment [151]. These materials, known as stimulus-responsive materials, change chemically or physically in response to external inputs. This approach is crucial in nanomedicine, because of its controlled and targeted drug release at sites of action, thereby minimizing adverse effects on healthy cells. Stimulus-responsive devices enhance pharmacological efficacy by releasing drugs at targeted sites in response to triggers such as pH, redox potential, light, temperature, ultrasound, and magnetic fields [152]. Multi-stimulus-responsive drug delivery systems are more effective in cancer therapy than single stimulus-responsive drug delivery systems, and consequently improve drug accumulation and release in targeted cancer cells, and lead to better tumor cell depletion [153, 154].

Recent developments include pH-sensitive lipid nanoparticles, which release their drug content in response to the tumor’s pH of approximately 6.5. This mechanism of selective release to target tissues amplifies the intensity of treatment and avoids undesirable adverse reactions [133].

The creation of stimulus-responsive nanoparticles greatly facilitates drug delivery for cancer therapy. The success of therapeutic drug delivery in response to internal and external signals is enhanced by these nanoparticles.

Table 2 summarizes various studies on LBNPs used in cancer therapies, including formulations, methods, and outcomes. NLCs loaded with 5-fluorouracil have been found to enhance skin permeation and achieve prolonged release for skin cancer treatment. Liposomes co-loaded with paclitaxel and carboplatin show enhanced targeting and diminished toxicity in ovarian cancer. Solid lipid nanoparticles containing docetaxel also exhibit improved efficacy in prostate cancer through targeted delivery. Overall, these studies highlight the potential of LBNPs to enhance drug delivery and therapeutic efficacy across various cancer types.

Current clinical trials

Clinical trials continue to evaluate the efficacy and safety of LBNP-based therapies, and many studies are focusing on the potential of LBNPs in combination with other treatment modalities. Several LBNP-based drugs have received approval for clinical use, including Doxil (liposomal doxorubicin), Marqibo (liposomal vincristine), and Onivyde (liposomal irinotecan). These formulations were specifically designed to address the limitations of traditional chemotherapeutics, such as poor solubility, rapid clearance, and systemic toxicity [162]. The most notable advancements in LBNP use for treating the most prevalent cancer types are listed in Table 3.

The clinical translation of LBNPs has achieved successes and faced challenges. Several LBNP-based formulations, such as Doxil (liposomal doxorubicin) and Marqibo (liposomal vincristine), have received regulatory approval and are currently in clinical use. However, the path to clinical relevance has encountered obstacles. Issues such as batch-to-batch variability, the need for extensive safety assessments, and the complexity of nanoparticle formulations have hindered the widespread use of LBNPs. This review discusses specific case studies of LBNP formulations that have successfully transitioned to clinical use and those that have faced setbacks, providing a comprehensive overview of the current landscape of LBNP clinical trials.

Challenges and future perspectives

LBNPs have been demonstrated to aid in treating cancer by enhancing precise, controlled drug delivery and achieving better therapeutic results. However, several challenges must be solved to increase their effectiveness. The primary challenge is scaling up LBNPs while maintaining the quality, stability, and reproducibility of the individual LBNPs. The intricate nature of LBNP compositions requires accurate control of parameters such as size, surface charge, and drug loading; consequently, mass production is complicated and expensive. Another major drawback is non-specific targeting and toxicity. Although LBNPs target only cancer cells, their active accumulation in healthy tissue can be damaging. Moreover, the diversity of tumors and their intricate microenvironments introduce further complications: for example, faulty blood vessels and interstitial fluid pressure hinder the penetration of LBNPs into targeted cells. Solutions under study include combinations of LBNPs and personalized medicine targets, including ligands or antibodies for active targeting and simultaneously stimulus-responsive LBNPs that target specific tumor environments and trigger the LBNPs to release their payloads.

Despite the potential for LBNPs to treat cancer, clinical translation of these nanomedicines has been encumbered. The major problems include difficulties in large-scale manufacturing without compromises regarding uniformity, stability, and systemic toxicity. In terms of clinical conversion, although many LBNP formulations have demonstrated effectiveness in preclinical stages, advancing to clinical use require regulatory approval and standardized techniques for characterization. In addition, the efficacy and safety of new LBNP therapy methods in large patient populations should be verified with clinical trials. Herein, we describe issues in clinical translation to assess the future use of LBNPs in cancer therapy, particularly regarding the integration of basic research concepts with those of medical practitioners and the regulatory environment. The absence of standardized characterization and regulatory policies for LBNPs might adversely affect their promotion. Increased regulatory efforts and improved analytical methods are necessary to ensure the safety and quality of LBNPs.

Elucidating these aspects to achieve incorporation of LBNPs into targeted and controlled drug delivery systems would help overcome existing constraints. The potential for overlapping LBNP use with other therapeutic options, including immunotherapy and radiotherapy, might have favorable effects and synergistically enhance desired outcomes. The endorsement and introduction of targeted approaches would provide greater research opportunities for developing techniques for improving LBNPs and achieving a smooth transition of LBNPs from bench to bedside in cancer therapy. Joint efforts by scientists, clinical practitioners, regulators, and the industry are required to bring new LBNPs with modern innovations and changes to market. In the hands of researchers, the ability to refine can help overcome existing barriers to engineering more effective therapies tailored to meet and exceed tumor requirements, further targeting precision cancer medicine to increase patient quality of life.

Encouraging results have been reported in treating cancer with LBNPs, thus indicating a need for further in-depth investigations. Such efforts would complement ongoing investigations aimed at refining systems by using recombinant proteins to enhance the release mechanisms of LBNPs, thereby producing more effective cancer therapeutics. A promising direction is applying LBNPs’ targeting approaches in cancer treatments by using a patient’s disease-related genetic profile to target the therapy for a particular type of cancer.

Understanding tumor molecular heterogeneity with the help of newly developed genomic and proteomic technologies has enabled identification of changes in tumor genes and related signaling, tumor markers, and antigens that can be targeted by LBNP-based therapies. Scientists hope to improve the efficiency of direct delivery of therapeutic agents to tumor sites by incorporating patient-specific biomarkers into LBNP design and targeting, thus decreasing adverse effects and enhancing anti-tumor efficacy. Another milestone in LBNP research is the enhancement of targeted delivery systems to one tumor population, specific cancer stem cells, or drug-resistant cells. These subpopulations often play crucial roles in tumor formation, metastasis, and improving the body’s defense mechanisms against treatment. Because tumor heterogeneity might potentially lead to problems in which resistant cancer subpopulations are not effectively destroyed, researchers have sought to modify LBNPs to specifically target and capture these subpopulations.

Continuing research is aimed at understanding resistance to LBNP-based therapies, including analysis of how multidrug resistance can be overcome by loading chemotherapeutic agents and resistance-modulating drugs into the same LBNP system. However, generating stimulus-responsive LBNPs that respond only to specific tumor microenvironmental signals or pH or redox changes might hinder microenvironmental evolutionary mechanisms and improve healing efficiency. As cancer nanomedicine advances, new approaches are designed for the formulation of LBNPs, and newer generations of technologies such artificial intelligence and machine learning-based workflows become available, the augmentation of LBNPs with these newer technologies will be essential for effective design and formulation, as well as clinical implementation. Using computational tools and models, researchers can increase the pace of finding specific LBNP-based treatments, strengthen the effectiveness of drug release kinetics and drug loading ability, and generally shorten the drug development cycle.

In conclusion, the future of LBNPs in cancer treatment is promising. Recent studies have focused on overcoming the disadvantages of these multi-functional drug delivery systems and exploring their benefits to achieve better patient care and quality of life.

Conclusion

LBNPs are a new generation of drug delivery systems for cancer therapy that confer enormous benefits over conventional classes of chemotherapeutic drugs. The fundamental properties of LBNPs, including a broad spectrum of encapsulated therapeutic activity, favorable solubility and bioavailability, and guided delivery to tumor tissue, have supported cancer nanomedicine. LBNP technology has continued to make strides in the investigation of drug delivery system subtypes, namely liposomes, SLNs, and NLCs, which provide a wide-ranging set of tools for treatment customization for specific cancer types or patient populations. LBNPs are highly versatile systems for incorporating both hydrophilic and hydrophobic drugs, thereby allowing co-delivery of combination therapies. Therefore, these particles may be used to enhance the efficacy of treatment options by overcoming drug resistance mechanisms, which pose challenges in cancer treatment. In addition, the opportunity to design LBNPs with targeting moieties on their surfaces has led to the development of targeted delivery systems that can specifically homogenize in tumor sites, thus minimizing adverse effects and facilitating the drug’s therapeutic index. LBNPs have high potential for future cancer treatment, through incorporation into state-of-the-art technologies such as personalized medicine and stimulus-responsive drug release. To achieve more individualized and efficient cancer treatments, researchers can use patient-specific biomarkers and engineer LBNPs designed in response to cues from the tumor microenvironment. Despite challenges in production scale-up, off-target effects, and a need for standardized characterization techniques, the application of LBNPs in cancer therapy appears bright. Ongoing clinical trials and research studies are beginning to pave the way to successful translation of these groundbreaking drug delivery systems from laboratory to bedside, thus offering hope for improved patient outcomes and increased quality of life.

In conclusion, LBNPs have shown significant potential in transforming cancer treatment. Their versatile nature, targeted delivery capabilities, and ability to overcome the limitations of traditional chemotherapy position LBNPs as a promising avenue for advancing cancer nanomedicine and enhancing the well-being of patients with cancer.

Declarations

Data availability statement

Data generated or analyzed during this study are available from the corresponding author upon request.

Authors’ contributions

The authors confirm the following contributions to the article. Study conception and design: ASC, PC; data collection: ASC, TP; analysis and interpretation of results: ASC, PC; draft manuscript preparation: PC, TP. All authors reviewed the results and approved the final version of the manuscript.

Financial support

None

Acknowledgments

All authors express special thanks to Mr. Jitender Joshi (President) and Prof. (Dr.) Dharam Buddhi (Vice Chancellor) at Uttaranchal University for their encouragement.

Conflicts of interest

No conflicts of interest.

List of abbreviations

(LBNPs) Lipid-based nanoparticles, (TEM) Transmission electron microscopy, (DLS) Dynamic light scattering, (Cryo-TEM) Cryogenic transmission electron microscopy, (SLNs) Solid lipid nanoparticles, (NLCs) Nanostructured lipid carriers, (NPS) Nano-plasmonic sensing, (PEG) Polyethylene glycol, (LPHNPs) Lipid-polymer hybrid nanoparticles, (PC) Phosphatidylcholine, (NP) Nanoparticles, (SCF) Supercritical fluid, (EPR) Enhanced permeability and retention, (Doxil) Liposomal doxorubicin, (Marqibo) Liposomal vincristine, (Onivyde) Liposomal irinotecan.

Graphical abstract

Highlights

• LBNPs have emerged as a groundbreaking method in cancer treatment, offering innovative drug delivery solutions that enhance therapeutic efficacy and minimize adverse effects.
• LBNPs have been shown to overcome the limitations of traditional chemotherapy, resulting in improved patient outcomes.
• The study explores various targeting strategies, including passive, active, and responsive delivery platforms, which direct LBNPs to tumors.
• Liposomes, nanostructured lipid carriers, solid lipid nanoparticles, and lipid-polymer hybrid nanoparticles each possess unique features beneficial for cancer therapy.
• The review highlights current challenges, possible future directions, and the potential of LBNPs in combination therapy to revolutionize cancer treatment further.

In brief

Lipid-based nanoparticles (LBNPs) have emerged as a transformative approach in cancer treatment, offering innovative drug delivery solutions that enhance therapeutic efficacy while minimizing adverse effects. This study explores the characterization, classification, synthesis, targeting strategies, and advantages of LBNPs, highlighting their potential to overcome the limitations of traditional chemotherapy and improve patient outcomes. As nanotechnology revolutionizes cancer therapy, the emergence of LBNPs as a promising strategy for targeted drug delivery brings optimism for the future of cancer treatment. The review provides a comprehensive assessment of the structure, groupings, production methods, focusing approaches, benefits, and recent advancements of LBNPs in cancer treatment while addressing current challenges and possible future directions. Liposomes, nanostructured lipid carriers, solid lipid nanoparticles, and lipid-polymer hybrid nanoparticles have unique features of interest for cancer therapy. They can be synthesized through various procedures, such as bulk nanoprecipitation, solvent-based emulsification, or microfluidics. LBNPs employ passive, active, and responsive targeting systems to direct drugs to tumors, improving drug release patterns and minimizing adverse effects, thus enhancing therapeutic efficacy. Their potential use in combination therapy offers hope for overcoming the shortcomings of traditional chemotherapy methods, with ongoing research expected to improve patient outcomes and overall quality of life in cancer care.