In the rapidly evolving landscape of drug delivery, BDSs stand out as a beacon of innovation, drawing inspiration from biological structures and processes to optimize therapeutic delivery. By mimicking nature, BDSs aim to overcome the myriad challenges associated with traditional drug delivery, ranging from off-target effects to limited bioavailability [5]. BDSs span a broad spectrum, from liposomal structures to protein-based nanoparticles and CMDNs [1,8,42,44]. While the promise of BDSs is undeniable, it’s imperative to evaluate their strengths and weaknesses in comparison with each other (Table 1).

Liposomes are spherical vesicles composed of phospholipid bilayers that can encapsulate a wide variety of therapeutic agents. Their biocompatibility arises from their resemblance to biological membranes, making them a preferred choice for drug delivery [45]. Despite their adaptability in drug loading, liposomes are not without limitations [46]. A critical issue pertains to their stability, which can be compromised during storage, necessitating the development of sophisticated stabilization strategies to ensure the longevity and efficacy of the liposomal formulation [47,48,49,50]. In vivo, liposomes may exhibit rapid clearance from the bloodstream, primarily due to opsonization and subsequent phagocytosis by the cells of the mononuclear phagocyte system [51,52]. This necessitates careful consideration of liposome size, surface charge, and surface modification with polymers such as polyethylene glycol (PEG) to extend their circulatory half-life [51,53].

Protein-based NPs, encompassing albumin NPs, protein-based nanocages, VLPs, and NDs, offer a versatile toolkit for enhancing drug delivery, each with distinct advantages and shared challenges. Albumin NPs utilize human serum albumin, which has a natural propensity to bind to various substances, thereby facilitating the transport of a wide range of molecules [54]. The biodegradability and lack of immunogenicity of albumin contribute to its appeal as a drug carrier. Notably, albumin has a unique ability to accumulate in tumor tissues due to the enhanced permeability and retention (EPR) effect, making it particularly useful for oncological applications [55,56]. However, the drug loading efficiency of albumin NPs can be unpredictable, and their interaction with the biological environment may sometimes lead to rapid clearance from the circulatory system. Despite this, the clinical success of albumin NPs is exemplified by the FDA-approved drug Abraxane, which is an albumin-bound form of paclitaxel used for the treatment of various cancers [57]. Protein-based nanocages are a novel form of protein NPs that offer a highly structured and uniform platform for drug delivery [58]. They are engineered by utilizing the self-assembling properties of certain proteins to form cage-like structures that can encapsulate therapeutic agents within their hollow interior [59]. This allows for precise control over the dosage and protection of the cargo from enzymatic degradation. However, the complexity of synthesizing these nanocages poses a significant challenge, potentially limiting their rapid deployment in clinical settings [60]. VLPs are multiprotein structures that mimic the organization and conformation of viruses but are devoid of viral genetic material, which mitigates safety concerns associated with live viral vectors. The repetitive, high-density display of antigens on their surface makes VLPs particularly effective as vaccine platforms, eliciting strong immune responses [11,61,62]. However, the production of VLPs is technically demanding, often requiring cell culture systems, and the scale-up for mass production can be challenging [63,64,65]. Nanodiscs are synthetic nanoscale particles that incorporate membrane proteins within a phospholipid bilayer stabilized by scaffold proteins. NDs provide a unique milieu for the study of membrane proteins in their near-native state, which is invaluable for drug discovery and development [66]. While they offer a controlled environment for membrane proteins, their therapeutic application as drug delivery vehicles is still nascent [30,67,68], with issues related to production scalability and drug loading capacity yet to be fully addressed. In a comparative context, while albumin NPs have achieved clinical use, protein-based nanocages and VLPs are still primarily in the research or early clinical trial stages. NDs, being relatively recent developments, and have not yet been extensively explored for therapeutic delivery but hold potential due to their unique ability to present membrane proteins and delivery of lipophilic drugs. Each of these protein-based NPs has its advantages in terms of specificity, biocompatibility, and targeting ability; however, they also face common challenges such as production complexity, stability, and potential immunogenicity.

Silk fibroin (SF) and gelatin (GA) epitomize the contrasting paradigms within BDSs, each with inherent strengths and challenges. SF is distinguished by its robust mechanical properties and sustained release potential, making it a quintessential candidate for structurally demanding applications such as in bone tissue engineering and targeted cancer therapies [69,70,71]. Nevertheless, its utility is occasionally circumscribed by intricate processing requirements and immunogenic concerns. Conversely, GA is celebrated for its facile chemical modifiability and hydrogel formation aptitude, characteristics that are pivotal for localized therapeutic delivery and tissue engineering scaffolds [72,73]. Yet, its application is sometimes compromised by inferior mechanical integrity, thermal instability, and the latent risk of pathogenic transmission [74]. The selection between SF and GA for DDSs is thus dictated by a nuanced balance between the therapeutic context and the material’s physicochemical congruity, with each material offering distinctive contributions to the diversifying landscape of biomimetic therapeutic delivery.

EVs and CMDNs represent two innovative approaches in the realm of biomimetic drug delivery, each leveraging the innate properties of cellular components. EVs, owing to their natural origin, can transport a wide variety of biomolecules and have the ability to cross biological barriers with a low risk of immune response, positioning them as promising vectors for regenerative medicine and targeted cancer therapies [18,75,76]. Nevertheless, isolating EVs with high purity remains a significant technical challenge [77,78,79]. CMDNs, on the other hand, utilize the unique attributes of cell membranes to cloak nanoparticles, enabling them to evade the immune system and increase delivery specificity [27,80,81]. This strategy has shown considerable promise in targeted drug delivery and immunotherapy, capitalizing on the natural homing abilities of cells. Both EVs and CMDNs still face substantial production complexities (EVs in terms of isolation and CMDNs with membrane extraction and nanoparticle integration).

Polysaccharides, a diverse group of biopolymers, including alginate, chitosan, hyaluronic acid, and dextran, play a pivotal role in the landscape of therapeutic delivery due to their inherent biocompatibility and tailored biodegradability [82,83]. Alginate, renowned for its gel-forming capabilities, is widely used in wound healing applications and as a matrix for cell encapsulation, benefiting from its gentle gelation conditions that preserve cell viability [84,85]. Chitosan, with its distinctive mucoadhesive properties and ability to open tight junctions [86], is exploited for enhanced mucosal delivery of drugs, offering improved bioavailability and prolonged retention at the site of administration. Hyaluronic acid, by virtue of its specific interaction with CD44 receptors [87], which are overexpressed in many cancer cells, has emerged as a targeted delivery vehicle, especially in the treatment of osteoarthritis, where it can provide both viscosupplementation and targeted relief [88]. Dextran, due to its excellent solubility and minimal toxicity, is employed in various drug delivery systems and as a plasma volume expander, with its iron-conjugated forms used to treat iron-deficiency anemia [89,90].

Despite these advantages, the application of polysaccharides is not devoid of challenges; their susceptibility to rapid degradation in vivo may limit their utility, and potential immunogenicity cannot be entirely discounted. Moreover, the batch-to-batch variability and the complexity of producing highly purified, well-characterized polysaccharides can impact the reproducibility and scalability of pharmaceutical products. Hence, while polysaccharides offer considerable benefits for drug delivery, their clinical application requires meticulous optimization to ensure efficacy, safety, and manufacturability.