Lipid-based nanomaterials have become a significant advancement in the field of drug delivery, providing notable advantages in the encapsulation and delivery of therapeutic agents. Among these, liposomal is a prominent example.²⁶ Liposomal nanoparticles represent a significant advancement in drug delivery, offering numerous benefits due to their unique structure and biocompatibility. These vesicles, typically composed of lipid bilayers, can encapsulate lipophilic, hydrophilic, and hydrophobic drugs, thus enhancing the therapeutic efficacy while reducing toxicity.^27,28 The flexibility in their design allows for controlled release, targeted delivery, and protection of the encapsulated drug from degradation, which is critical for treating diseases like cancer and infections.²⁹

The liposomal formulation ensures that drugs are delivered precisely to the target site, minimizing systemic side effects and improving the pharmacokinetic profiles of drugs. For example, Doxil®, a liposomal formulation of DOX, has demonstrated reduced cardiotoxicity compared to its free drug counterpart.³⁰ There are several studies highlighting the efficacy of liposomal intervention in drug delivery. For instance, Una et al. explored the use of a novel liposomal delivery system for dexamethasone phosphate (DXM-P) to treat collagen-induced arthritis in rodents, aiming to separate the therapeutic benefits of glucocorticoids from their typical side effects. The liposomal DXM-P provided a prolonged anti-inflammatory effect with fewer side effects compared to the free form of the drug. Notably, a single dose of the liposomal formulation was as effective as multiple daily doses of the free drug but resulted in less suppression of the hypothalamus-pituitary-adrenal (HPA) axis, lower impact on blood glucose levels, and milder hematological changes. Specifically, a single dose of liposomal DXM-P, especially at 4 mg/kg, was sufficient to reduce joint swelling for up to 7 days, whereas the free form required daily dosing to achieve a similar effect, as shown in Figure 2. Also, liposomal DXM-P was more successful in decreasing collagen breakdown, as indicated by lower pyridinoline levels in urine, suggesting better protection against joint tissue degradation, as highlighted in Figure 2. The liposomal DXM-P offers significant advantages over free DXM-P, including a sustained anti-inflammatory effect with fewer doses, reducing the need for daily administration. It minimizes typical glucocorticoid side effects, such as suppression of the HPA axis and hyperglycemia, which are more pronounced with free DXM-P. The liposomal form also allows for better targeting, accumulating mainly in the spleen and avoiding excessive liver exposure, resulting in higher therapeutic efficacy with lower drug amounts and fewer side effects. This suggests that liposomal DXM-P could offer a more targeted and safer approach to treating inflammatory diseases like arthritis.³¹

Lipid-based drug delivery systems have evolved significantly, extending beyond the traditional liposome-based models to encompass a range of innovative approaches, each offering distinct advantages for therapeutic applications. Solid lipid nanoparticles and nanostructured lipid carriers are particularly noteworthy for their ability to provide controlled drug release and enhanced stability, especially in the context of poorly water-soluble drugs.³² The use of micelles, composed of amphiphilic molecules, has proven effective in increasing the solubility and bioavailability of hydrophobic drugs.³³ Transfersomes, recognized for their ultra-deformability, have emerged as a promising option for transdermal drug delivery, enhancing the penetration of therapeutic agents through the skin.³⁴ Additionally, niosomes, which are structurally similar to liposomes but formulated from non-ionic surfactants, offer enhanced stability and versatility, making them suitable for delivering a wide array of drugs.³⁵ Collectively, these diverse lipid-based delivery systems are instrumental in advancing drug delivery technologies, contributing to improvements in drug solubility, stability, and targeted therapeutic efficacy.

Polymeric nanoparticles (PNPs), which are submicron-sized colloidal particles typically ranging from 10 to 1,000 nm, have emerged as a promising platform in the realm of drug delivery systems. ³⁶ These nanoparticles are made from polymers that are both biodegradable and biocompatible, incorporating natural substances like chitosan and alginate, along with synthetic polymers such as PLGA and polycaprolactone.³⁷ The primary design of PNPs is to encapsulate therapeutic agents, offering protection from degradation while simultaneously enhancing their stability, bioavailability, and targeted delivery. One of the defining features of PNPs is their capacity to encapsulate a broad spectrum of therapeutic agents, including small molecules, proteins, peptides, and nucleic acids, thus enabling controlled and sustained drug release.⁵ This encapsulation strategy not only safeguards drugs from premature degradation within the biological milieu but also prolongs their circulation time within the bloodstream. Furthermore, PNPs can be engineered to respond to specific stimuli—such as pH fluctuations, temperature changes, or enzymatic activity—commonly found in pathological environments like tumors or inflamed tissues. This stimulus-responsive release ensures that the therapeutic agents are delivered precisely where they are needed, maximizing efficacy while minimizing off-target effects.³⁸

A significant advantage of PNPs lies in their ability to target specific tissues or cells, which substantially reduces the systemic side effects often associated with conventional drug delivery methods. By functionalizing the surface of PNPs with biomolecules, antibodies, or specific ligands that can recognize and bind to target cell receptors, drugs can be selectively delivered to diseased cells while sparing healthy tissues.²¹ This targeted approach is particularly beneficial in cancer therapy, where PNPs can direct chemotherapeutic agents specifically to tumor cells, thereby reducing the collateral damage to normal tissues and minimizing adverse effects. Compared to traditional drug delivery systems, PNPs offer several notable benefits. They significantly improve the bioavailability of drugs, particularly hydrophobic molecules that are otherwise plagued by poor solubility and absorption.³⁹ The polymer matrix of PNPs allows for controlled and sustained drug release, thereby reducing the frequency of dosing and improving patient compliance.³⁹ The polymer matrix of PNPs allows for controlled and sustained drug release, thereby reducing the frequency of dosing and improving patient compliance.³⁹ Additionally, the encapsulation of drugs within PNPs shields them from harsh biological environments, such as the acidic conditions of the gastrointestinal tract or enzymatic degradation in the bloodstream—this is particularly crucial for the delivery of sensitive biomolecules like proteins and nucleic acids.⁴⁰ Moreover, PNPs take advantage of the enhanced permeability and retention (EPR) effect observed in tumor tissues. The leaky vasculature and impaired lymphatic drainage characteristic of tumors allow nanoparticles to preferentially accumulate at the tumor site, thereby improving drug delivery and enhancing therapeutic efficacy while reducing systemic toxicity. This targeted accumulation, coupled with controlled drug release, minimizes the exposure of non-target tissues to therapeutic agents, leading to a better safety profile and fewer side effects.⁴¹

In their 2014 study, Snipstad et al. investigated the efficacy of PNPs in enhancing the intracellular delivery of hydrophobic drugs, using Nile red as a model compound. The researchers encapsulated Nile red within poly(butyl cyanoacrylate) (PBCA) nanoparticles and observed a significant increase in drug uptake by cells compared to the free drug. This enhancement in drug uptake was quantitatively confirmed using flow cytometry, as illustrated in Figure 3 (a) and (b)where encapsulated Nile red exhibited markedly improved cellular uptake. Furthermore, confocal laser scanning microscopy provided visual confirmation of this increased uptake. The microscopy images in Figure 3 (f), (g), and (h) clearly demonstrated that Nile red, when encapsulated within the PBCA nanoparticles, was taken up by cells more effectively when compared to the free drug in Figure 3 (c), (d), and (e). This enhanced uptake was attributed to a mechanism of contact-mediated transfer, where the nanoparticles directly delivered the drug into the cytosol, effectively bypassing the traditional endocytosis pathway and avoiding lysosomal degradation. This study underscores the potential of PNPs in delivering a hydrophobic drug, particularly in challenging therapeutic areas such as cancer treatment. By enhancing intracellular delivery and avoiding degradation pathways, PBCA nanoparticles can improve the efficacy of hydrophobic drugs, providing a promising strategy for the development of more effective cancer therapies.⁴²

Inorganic nanoparticles are engineered from materials such as metals and oxides that can be tailored to enhance the delivery of drugs, particularly in challenging contexts like cancer treatment and chronic diseases.⁴³ Inorganic nanoparticles such as gold nanoparticles (AuNPs), silver nanoparticles (AgNPs), and magnetic nanoparticles (MNPs) are gaining prominence due to their unique properties.^44,45 Gold nanoparticles, for example, are known for their excellent biocompatibility and ease of surface modification, which allows for targeted drug delivery and imaging. Silver nanoparticles, while widely recognized for their antimicrobial properties, also show promise in cancer treatment, where they can induce cytotoxic effects through mechanisms such as reactive oxygen species generation. MNPs, typically composed of iron oxide (Fe3O4), offer the dual advantage of drug delivery and hyperthermia treatment, where they are channeled to the site of tumor growth with magnetism and then heated to kill cancer cells.^44,45

One of the primary advantages of using inorganic nanoparticles in drug delivery is their biodegradability, particularly when combined with polymers like PLGA. Biodegradable nanoparticles gradually break down within the body, releasing the drug that is encapsulated in a controlled manner, which is crucial for maintaining therapeutic levels of the drug over extended periods. This sustained release reduces the frequency of drug administration and minimizes side effects, making treatment more manageable for patients.⁴⁶ Another significant benefit of the ability of inorganic nanoparticles is specificity, where the nanoparticle can target specific tissues and cells. This targeting capability can be achieved through surface modifications, such as PEGylation, or by attaching targeting ligands that recognize specific receptors on the surface of cancer cells. For instance, gold nanoparticles can be conjugated with antibodies or peptides that specifically bind to tumor markers, ensuring that the therapeutic agent is delivered directly to the cancer cells, sparing healthy tissues from the cytotoxic effects.⁴⁷ Moreover, the small size and high surface-area-to-volume ratio of these nanoparticles allow for efficient drug loading and delivery. The EPR effect is a phenomenon utilized in cancer therapy where nanoparticles can passively accumulate in tumors. This effect occurs because the leaky vasculature of tumors allows nanoparticles to penetrate and remain within the tumor tissue, facilitating targeted drug delivery. This property is particularly beneficial in delivering chemotherapeutic drugs, which are often limited by their non-specific distribution in the body.⁴¹

In a study by Rahul et al., the efficacy of doxorubicin-loaded hollow gold nanospheres (Dox@HAuNS) for treating liver cancer was explored through a combination of photothermal ablation (PTA) and chemoembolization. Utilizing a rabbit model of liver cancer, the researchers demonstrated the potential of this dual therapeutic approach. The Dox@HAuNS nanoparticles were delivered directly into the tumor via trans-arterial injection, followed by near-infrared laser irradiation. Rabbits that received the PTA in combination with the nanoparticle formulation exhibited significant tumor reduction, as shown in Figure 4a. By the 14th day, all three variations of the nanoparticle treatment had significantly reduced tumor volume, with the most pronounced initial effect observed in the Dox@HAuNS + PTA group, as depicted in Figure 4 (b) and c. This approach facilitated targeted drug delivery and localized heating, leading to substantial tumor reduction. The study underscores the potential of gold nanoparticles to enhance cancer treatment by integrating chemotherapy with thermal ablation.⁴⁸

Apart from the above-mentioned nanomaterial-mediated drug delivery systems, stimuli-responsive, carbon-based, biological, and hybrid nanomaterials are other choices for delivery systems. Stimuli-responsive nanomaterials are engineered to react to specific environmental triggers like pH, temperature, or light, enabling controlled drug release precisely at the target site. This targeted approach reduces side effects and increases treatment efficacy, particularly in cancer therapies.⁴⁹ Carbon-based nanomaterials, like carbon nanotubes and graphene, excel in drug delivery due to their high surface area and ability to be functionalized, improving solubility, biocompatibility, and targeted delivery. These materials are especially promising for delivering chemotherapeutics and genetic materials while minimizing harm to healthy cells.⁵⁰ Biological nanomaterials leverage the inherent biocompatibility of natural molecules, facilitating immune system evasion and improving the effectiveness of vaccines and gene therapies.⁵¹ Hybrid nanomaterials combine the advantages of different nanomaterials, enhancing drug delivery through synergistic effects, making treatments more efficient, and reducing potential side effects.⁵²

The EPR phenomenon is a pivotal mechanism in nanoparticle-mediated drug delivery, particularly in the treatment of cancer, which is a major mechanism used for the passive targeting of drugs. Matsumura et al. were the first to report the EPR effect, demonstrating how it enables nanoparticles to accumulate in tumors. This accumulation occurs due to the leaky vasculature and poor lymphatic drainage characteristic of tumors, which is typically more permeable than that of normal tissues due to its rapid and abnormal angiogenesis.⁵⁴ The EPR effect allows nanoparticles to accumulate selectively in tumor tissues, enhancing drug concentration at the target site while minimizing systemic exposure. Nanoparticles, due to their small size and modifiable surface properties, can navigate through the leaky blood vessels of tumors and evade rapid clearance by the lymphatic system. This passive targeting mechanism is particularly advantageous for delivering chemotherapeutic agents, as it increases the therapeutic index and reduces the side effects associated with conventional chemotherapy. The EPR effect has been widely studied and forms the basis for many nanoparticle-based drug delivery systems currently under development, offering a promising approach for improving the efficacy of cancer treatments while minimizing damage to healthy tissues.^55,56 One of the profound applications was the drug Doxil, a liposomal formulation of DOX, which is designed to exploit the EPR effect to accumulate preferentially in tumor tissues. This formulation has been shown to significantly enhance the delivery of DOX to tumors, improving therapeutic outcomes while reducing side effects compared to the free drug.²²

Active targeting via ligand-directed nanoparticles represents a significant advancement in precision medicine, enabling the delivery of therapeutic drugs or agents directly into those cells that are diseased. This approach leverages the specificity of ligands, such as antibodies, peptides, or small molecules, which are conjugated to the surface of nanoparticles. These ligands are designed to bind selectively to receptors that are overexpressed on target cells, such as cancer cells or cells within inflamed tissues. Upon binding, the ligand-nanoparticle complex can be internalized through receptor-mediated endocytosis, allowing for the localized release of the drug within the target cell. This method enhances the efficacy of treatment by concentrating the drug at the site of disease, reducing the required dosage, and minimizing systemic toxicity. The precision and effectiveness of ligand-directed nanoparticles make them a promising tool for targeted drug delivery application, offering hope for more effective treatments with fewer side effects.^17,56 For instance, a study by Elena et al. explores the development of terpolymer-based nanocapsules functionalized with folic acid to selectively target cancer cells that overexpress folate receptors. These nanocapsules are engineered to deliver DNA specifically to cancer cells, offering a more targeted and controlled release mechanism. By focusing on direct delivery to cancer cells, this approach seeks to enhance the efficacy of cancer therapy, minimizing the impact on healthy cells and reducing the side effects typically associated with conventional treatments [57].

Stimuli-responsive drug release mechanisms in nanoparticle-mediated drug delivery represent a sophisticated approach to achieving precise and controlled therapeutic outcomes. These mechanisms leverage the unique environmental conditions of diseased tissues, such as pH, temperature, and enzymatic activity, to trigger the release of drugs from nanoparticles at the target site.³⁸ This ensures that the drug is released specifically where it is needed, minimizing off-target effects. For instance, pH-responsive nanoparticles are designed to release their cargo in acidic environments, such as those found in tumor tissues or intracellular compartments like endosomes and lysosomes.⁵⁸ Temperature-responsive nanoparticles, on the other hand, release drugs in response to elevated temperatures, a common feature of inflamed or cancerous tissues.⁵⁹ Similarly, enzyme-responsive nanoparticles release their therapeutic load when exposed to specific enzymes that are overexpressed in diseased tissues.³⁸ These stimuli-responsive systems not only enhance the therapeutic efficacy of the drug but also allow for a reduction in the overall dosage required, thereby decreasing potential side effects. The development and refinement of these mechanisms continue to be a focal point in the advancement of targeted and personalized medicine, offering promising prospects for the treatment of complex diseases.³⁸

Mucoadhesion-based nanoparticle drug delivery systems allow for prolonged retention at mucosal sites and enhance drug absorption. This characteristic is particularly advantageous for drugs targeting mucosal tissues such as the gastrointestinal tract, nasal cavity, and eyes.⁶⁰ Chitosan, a biopolymeric material, is commonly used in these systems due to its superior mucoadhesive properties. It enhances adhesion to the mucus layer through electrostatic interactions with the negatively charged mucin, resulting in increased residence time and sustained drug release. Nanoparticles with mucoadhesive properties, such as those formulated with chitosan or its derivatives, can be administered via various routes, including oral, nasal, ocular, and pulmonary pathways. These nanoparticles interact effectively with mucosal tissues, improving drug bioavailability by shielding the drug from enzymatic degradation and facilitating closer contact with the absorption site.⁶¹ Additionally, the sustained release enabled by mucoadhesion helps maintain therapeutic drug levels over extended periods, thereby reducing dosing frequency and enhancing patient compliance. Particle size and surface charge are two critical factors that influence the effectiveness of mucoadhesive nanoparticles in drug delivery. These factors play a significant role in determining the interaction between nanoparticles and mucosal tissues, impacting drug absorption and retention.⁶² Due to these properties, mucoadhesive nanoparticles offer a versatile platform for targeted and controlled drug delivery applications. One of the best examples is a study demonstrated by Jan et al., in which the team developed a mucoadhesive nanoparticulate drug delivery system using thiolated chitosan nanoparticles for targeted drug release in the urinary bladder. The system enhances drug adhesion to the bladder mucosa and provides sustained release, potentially improving the effectiveness of intravesical therapies for bladder diseases like interstitial cystitis.⁶³