Types of nanomaterials used as drug delivery systems

A wide range of nanostructures has been investigated for drug delivery applications. While some of these nanomaterials have reached a more advanced stage of clinical development, new alternatives are continuously being explored, with the potential to enrich and diversify therapeutic options in the future. These nanomaterials differ in composition, structure and functionality, features that confer specific advantages for various biomedical applications [15,26]. Figure 2 illustrates some of the traditionally used nanomaterials for drug delivery, grouped into four main categories. In the following sections, each class of material is addressed individually, with particular emphasis on subtypes that have demonstrated more advanced clinical translation. In addition, emerging materials are briefly discussed to highlight their potential and to provide a forward-looking perspective on future developments.

Figure 2.: Types of nanomaterials used as drug delivery systems. Grouped into four main categories: polymeric nanoparticles, lipid-based nanoparticles, inorganic (also referred to as non-polymeric) nanoparticles and hybrid systems. Created by the authors with BioRender.com based on the synthesis of the literature reviewed in this article

Polymeric-based nanomaterials

Polymers are distinguished from other drug-delivery vectors, such as lipids or metals, primarily because of their versatility [65,66]. The ability to incorporate diverse functional groups, together with precise control over size and shape, confers polymers a broad range of functionalities and applications, as is described in the subsequent section [66,67].

Polymeric nanoparticles

Polymeric nanoparticles, composed of either synthetic or natural polymers, assemble biocompatible and biodegradable materials that allow precise control over both the release of encapsulated therapeutic agents and surface drug delivery. Polymeric nanoparticles can be prepared using various methods from either natural polymers, such as chitosan, gelatine, albumin, or alginate, or synthetic polymers such as poly (D,L-lactic acid), poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) and their copolymers [68,69]. These materials can modulate drug release in response to environmental stimuli, such as temperature or pH [70]. The degradation of certain polymers (e.g. PLGA) yields non-toxic products like CO₂ and H₂O, which are naturally eliminated, thus contributing to their favourable safety profiles [71].

From a translational perspective, the most solid example of the clinical advancement of polymeric nanoparticles is Abraxane®, an albumin-bound nanoparticle formulation of paclitaxel, approved alone or in combination, for the treatment of metastatic breast cancer, non-small cell lung cancer, and metastatic pancreatic adenocarcinoma, which has demonstrated enhanced tolerability and clinical utility compared to free drug administration [72,73]. Although proteins are natural polymers, protein-based nanoparticles such as Abraxane® are often classified in the literature as a distinct subtype of nanoparticles (protein nanoparticles).

Polymeric nanoparticle systems have attracted considerable attention in preclinical and clinical research and have been explored as carriers for small-molecule drugs, peptides, and nucleic acids, as well as for theragnostic applications. Polymeric nanoparticles hold significant promise for transforming cancer therapy into more effecttive and personalized treatments through ongoing clinical evaluation and material innovation [65,66,74,75]. For an in-depth description of polymeric and polymer-related nanoparticles, readers may refer to previously published reviews [65,67,76,77].

Drug-polymer conjugates

A different type of polymer-based platform involves the covalent linking of polymers to small molecules. This chemical conjugation increases molecular weight, thereby altering distribution and cellular affinity. Additionally, these conjugates improve stability, solubility and permeability. In the presence of pH-sensitive linkages, drug-polymer conjugates can release the molecules at specific sites, enhancing targeted delivery [68,78].

A clinically relevant example of this strategy is FYARRO®, an albumin-bound conjugate of sirolimus approved for the treatment of malignant perivascular epithelioid cell tumours. This conjugation enables the systemic delivery of a poorly soluble molecule while improving tolerability and clinical utility. Other examples include early clinical candidates such as PK1 (HPMA-doxorubicin) and NC-6300 (epirubicin-polymer conjugate), evaluated in Phase I clinical studies for solid tumours. Beyond oncology, conjugates such as APL-2 (pegcetacoplan) have advanced to Phase III trials in haematological disorders, further illustrating the translational breadth of polymer-drug conjugation strategies [79].

Micelles

Micelles are colloidal structures formed through the self-assembly of amphiphilic molecules in solution, utilized for their ability to enhance the solubility and stability of hydrophobic drugs. The micellar constituents are organized into spherical structures, with hydrophilic groups surrounding the hydrophobic core, thereby encapsulating hydrophobic drugs within their core [68,80].

Genexol® is a polymeric micellar formulation of paclitaxel approved for the treatment of breast cancer, which has demonstrated enhanced antitumour activity and increased tumour tissue accumulation compared with free paclitaxel and earlier paclitaxel formulations. In addition, this micellar system has shown encouraging clinical outcomes in multiple trials for the treatment of breast, lung, and ovarian cancers [65,81,82]. Other advanced micellar formulations under clinical evaluation include NK105, NK012, NC-6004, NC-401, NK911, CPC634, and Nanoxel M®, which are currently in different phases of clinical development and have reported promising improvements in safety and efficacy profiles across various oncological indications [83,84].

Dendrimers

Dendrimers are highly branched and compartmentalized nanopolymers that exhibit a uniform and well-defined three-dimensional structure [64,85]. They typically range in size from 1 to 5 nm and are capable of efficiently encapsulating molecules within their internal cavities. The terminal groups on dendrimer surfaces can be chemically modified to enhance biocompatibility, solubility and permeability, or to enable active targeting [68]. In preclinical studies, dendrimers have been explored as carriers for both small-molecule drugs and biomacromolecules, including nucleic acids, peptides, and vaccines. Structurally, they are commonly synthesized from synthetic monomers or copolymers such as poly(amidoamine), poly(propyleneimine), and poly(ethylenimine), although dendritic or hyperbranched architectures based on biopolymers have also been reported [86,87].

Advancing from preclinical research, dendrimers have demonstrated clinical translation, with several systems progressing to marketed products and advanced clinical trials. Dendrimer-based formulations are currently marketed for the prevention and treatment of viral and bacterial infections, including sexually transmitted diseases and respiratory viruses, such as VivaGel™ for bacterial vaginosis and human immunodeficiency virus prevention, and VIRALEZE™ as an intranasal antiviral formulation against respiratory viruses [88,89]. In parallel, multiple dendrimer-based therapeutics have advanced into Phase I-II clinical trials for oncological and inflammatory indications [90]. More recently, dendrimer platforms have expanded into the field of neuroinflammation and neurodegenerative disorders, with active clinical studies evaluating their potential both as therapeutic agents and, to a lesser extent, as diagnostic tools capable of reaching the central nervous system [91].

Emerging polymeric-based nanomaterials

Other polymeric-based nanomaterials have demonstrated strong preclinical promise; however, their clinical translation remains limited to date. Nevertheless, these platforms represent opportunities for further development due to specific advantages over conventional nanostructures. Representative examples include nanogels, polymersomes, and stimuli-responsive or polymer-hybrid nanocarriers, including polymer-lipid hybrid systems [68,92,93]. As the present work focuses on nanocarriers with more advanced clinical translation, these systems are not discussed in detail here. Readers interested in these platforms may refer to the extensive body of existing literature on the subject [94-96]. Further research aimed at identifying and overcoming current limitations, as well as expanding the understanding of their applicability, may ultimately support their progression toward clinical adoption of these emerging nanomaterials [94,97].

Inorganic nanomaterials

Inorganic nanomaterials have attracted considerable interest in the biomedical field due to their unique physicochemical, electromagnetic, optical and mechanical properties [17,98]. Although the application of inorganic nanomaterials as delivery agents for antibodies, nucleic acids, peptides and small molecules has been explored, their clinical translation remains limited, primarily due to concerns regarding long-term safety [98,99].

Drug nanocrystals

Nanocrystals are primarily composed of crystalline active pharmaceutical ingredients, with minimal use of stabilizing agents at low concentrations. These systems are applied to poorly soluble drugs, where their nanocrystalline form improves apparent aqueous solubility and bioavailability due to the improved surface-to-volume ratio. These features allow nanocrystals to achieve higher drug loading and concentration efficiency [68,100]. Some examples of marketed products consisting of nanocrystal formulations include Cabenuva® (Cabotegravir), Focalin XR® (Dexmethylphenidate hydrochloride) or IVEMEND® (Fosaprepitant) [101].

Nanocrystal formulations have shown success enabling clinically meaningful shifts in therapeutic use by unlocking new dosing paradigms or routes of administration. For example, antiretroviral nanocrystal/nanosuspension formulations (e.g. cabotegravir and rilpivirine) were specifically designed to support long-acting injectable regimens, addressing adherence limitations associated with daily oral therapy [102,103]. Similarly, nanoparticulate fenofibrate formulations reduce food-related variability in exposure, allowing more flexible dosing [104]. Beyond these benefits, nanocrystal reformulation represents a lifecycle-management strategy that may facilitate drug repurposing by overcoming solubility- and exposure-limited development [105,106].

Metallic nanoparticles

These nanomaterials have diameters between 1 and 100 nm and are typically composed of metals such as gold, cobalt, nickel, iron and their oxides. They can be readily synthesized and modified to decorate their surface with various molecules, including small molecules and biomolecules such as DNA and proteins [68,107]. These particles are biocompatible and stable. In addition, their magnetic properties allow them to be guided to specific locations in the body using external magnetic fields [98]. Metallic nanoparticles have both therapeutic and diagnostic applications, primarily in the field of oncology [98,108].

Approved applications of this type of nanocarrier include Nanobiotix®, which comprises hafnium oxide nanoparticles designed to enhance radiotherapy by promoting higher local energy accumulation in tumour tissues [101]. Another example is Nanotherm®, a formulation based on superparamagnetic iron oxide nanoparticles that enables magnetic hyperthermia; once the nanoparticles accumulate within the tumour environment, applying a magnetic field induces localized heating, leading to thermal destruction of tumour tissue [109].

Emerging inorganic nanomaterials

Despite extensive preclinical development and attractive physicochemical properties, several inorganic nanomaterials have been widely studied but have not yet achieved widespread clinical translation as drug delivery platforms. Among these, silica-based nanoparticles, carbon nanotubes, nanodiamonds, and quantum dots have received considerable research attention due to their versatility and tunability, which derive from their distinct structural, physical, and functional characteristics; however, their clinical use remains limited. Collectively, promising candidates illustrate the gap between technological promise and clinical implementation within inorganic nanomaterials [108,110-114].

Lipid-based nanomaterials

As discussed in the Evolution of the pharmaceutical market for nanoparticles section, current market trends indicate a growing relevance of lipid nanoparticles in clinical applications. This growing interest reflects their excellent biocompatibility and inherent compatibility with biological tissues, stemming from their similarity to cell membranes [115-117].

Liposomes

Liposomes are spherical structures with a lipid bilayer surrounding an aqueous core. They were the first lipid-based nanocarriers described and are perhaps the most representative of them [118,119]. Their structure allows them to encapsulate both hydrophilic and hydrophobic molecules, incorporated within the aqueous core or the lipid bilayer, respectively. Liposomes can fuse with cell membranes, releasing their contents directly into the cytoplasm, making them effective carriers for selective therapy delivery. Liposomes may be unilamellar or multilamellar, depending on the number of lipid bilayers they contain [68,120].

These carriers have been employed in therapeutic applications such as tumour detection and treatment, antibacterial therapy, vaccination and even targeted drug delivery to the brain. Surface modifications, such as coating with functionalized polymers or polyethylene glycol (PEG) chains, facilitate targeted distribution and improve circulation time in biological systems [68].

As previously mentioned, Doxil® represents a paradigm shift in the clinical impact of liposomal formulations, and, more broadly, of nanotechnology, on drug delivery. By significantly improving the pharmacokinetic profile and reducing toxicity relative to free doxorubicin, the liposomal nanocarrier directly enhanced clinical tolerability and enabled the expansion of therapeutic indications for a well-established anticancer agent [18,19,121]. Other examples of well-established liposomal clinical platforms include Ambisome® (amphotericin B), which is considered the standard medication for severe systemic fungal infections [122], or Vyxeos® (daunorubicin and cytarabine) approved for the treatment of acute myeloid leukaemia [123], among others.

Ionizable lipid nanoparticle

Ionizable lipid nanoparticles (i-LNPs) represent a more recent class of delivery systems that have gained increasing relevance alongside the development of nucleic acid delivery technologies [124,125]. Their use has become so standardized for this purpose that, in this context, they are often referred to simply as lipid nanoparticles (LNPs) [126-131]. They constitute the most clinically advanced delivery systems for maintaining the stability of therapeutic nucleic acids and enabling the efficient delivery of siRNA and mRNA [132-135], as well as in CRISPR-Cas9 and other gene-editing applications [136-138].

Because of their relative novelty, some reviews in the field of lipid nanoparticles do not yet recognize them as a distinct category, which can lead to LNPs being mistakenly classified as liposomes or even NLCs [68,139]. However, i-LNPs display clear structural and functional distinctions from other lipid-based nanoparticles [125,140]. They are composed of four main lipid components: ionizable lipids, phospholipids, cholesterol, and PEGylated lipids [129,141].

At acidic pH, ionizable lipids carry a positive charge, enabling electrostatic complexation with negatively charged nucleic acids by pH adjustment during manufacturing. However, they are neutral at physiological pH, which helps minimize toxic effects during systemic circulation [124,125,129]. After internalization and subsequent endosomal acidification, i-LNPs structure becomes unstable due to electrostatic repulsion and therefore releases their cargo into the cytoplasm via endosomal escape, a crucial step that protects RNA from degradation and allows the nucleic acid to reach its intracellular target [128,142,143].

Illustrating the advancement of this specific type of nanovehicle, Onpattro®, the first siRNA-based product delivered via ionizable lipid nanoparticles, was approved in 2017 for the treatment of hereditary transthyretin amyloidosis [144,145]. In 2020, Comirnaty®, an mRNA vaccine against SARS-CoV-2, received emergency approval for global immunization in response to the COVID-19 pandemic [146,147]. In 2023, Casgevy® received regulatory approval as the first CRISPR-Cas9-based gene-editing therapy for sickle cell disease, reinforcing the position of ionizable lipid nanoparticles as clinically validated platforms for advanced medicines [22].

Lipid nanocarriers with limited clinical translation

SLN and NLC were developed earlier than ionizable lipid nanoparticles and have been extensively investigated across diverse preclinical applications and drug classes [119,148,149]. However, their clinical translation for systemic drug delivery has remained limited, despite the large number of preclinical studies and patented formulations [150-152]. This has been mainly attributed to crystallinity-driven drug expulsion and physical instability, including polymorphic transitions and formulation-dependent leakage, which are partially mitigated in NLC [153,154]. In addition, challenges related to long-term stability, scale-up, and reproducibility remain significant barriers compared with more industrially mature platforms such as liposomes and ionizable lipid nanoparticles [155-157].

Hybrid systems as emerging nanomaterials applied to nanomedicine

Hybrid nanoparticles, which merge materials of diverse origins to optimize their characteristics, are also found in various applications [158]. For example, hybrid nanoparticles may be metal-lipid [159], lipid-polymer [160] or carbon-polymer [161]. These offer the advantage of creating synergy among the components, improving attributes such as stability, adaptability of manufacturing methods, drug release efficiency and biocompatibility, thereby optimizing performance in therapeutic or diagnostic applications [158,162]. Over the coming years, research and applications involving these materials are expected to expand, potentially leading to the emergence of new nanomaterials for biomedical exploration [163,164].

In general, each type of nanomaterial is characterized by unique properties that confer suitability for specific diagnostic or therapeutic applications [25,165]. The engineering and strategic exploitation of these properties have enabled the overcoming of translational barriers, driving the progression from experimental concepts to clinically validated therapeutic options with impact on disease treatment and the pharmaceutical market.