Peptide-Based Nanocarriers: Targeted Drug Delivery Strategies and Challenges in Clinical Translation
Background
Drug delivery systems are being developed in nanomedicine to address limitations of existing therapies, including toxicity in non-target tissues and low bioavailability. This review of the design and applications of peptide-based nanocarriers discusses the potential of targeted delivery alongside the limited progress toward clinical translation. Most remain at the preclinical stage, so the promise of these delivery technologies should not be interpreted as evidence of therapeutic benefit in patients.
Published in the International Journal of Nanomedicine, the review synthesizes advances in the design, manufacture, and therapeutic applications of peptide-based nanocarriers. The authors surveyed literature from 2016–2025, examining peptide incorporation strategies, nanocarrier platforms, and recent design trends. It does not report a new patient trial or test the efficacy of a single formulation.
Key Findings
The review groups peptides by role: target-recognition ligands, structural components of carriers, and elements that respond to environmental stimuli. Even when a peptide is directly linked to a drug, the resulting conjugate should be distinguished from peptide-based nanocarriers if it does not include a nanoscale carrier.
The main approaches to incorporating peptides are physical encapsulation, chemical conjugation, and self-assembly. Physical encapsulation places peptides inside a carrier to protect them from degradation and control their release. In chemical conjugation, peptides are covalently attached to the carrier surface or structure. With self-assembly, peptides form nanostructures themselves or stabilize carriers in combination with other materials. Platforms discussed include liposomes, solid lipid nanoparticles, dendrimers, polymeric micelles, mesoporous silica nanoparticles, and hybrid systems.
Target recognition and drug release are distinct design challenges. For example, RGD peptides are used as target-recognition elements that bind integrin receptors. By contrast, elements responsive to pH, enzyme activity, or redox conditions can be designed to release drugs in the local environment. Not every peptide nanocarrier performs both functions.
The review also covers examples in which structurally modified designs, including cyclic and stapled peptides, improved stability, target affinity, and bioavailability. These benefits must be verified for each formulation. The authors note that D-amino acid substitution may increase resistance to enzymatic degradation while reducing biological activity.
Implications and Outlook
Peptide-mediated targeting and physicochemical optimization of carriers are being used in delivery research for cancer, neurological disorders, infectious diseases, and inflammatory conditions. The review also covers delivery of small interfering RNA (siRNA), messenger RNA (mRNA), and CRISPR gene-editing tools (CRISPR-Cas9). These applications point to the possibility of delivering diverse therapeutic agents, but they do not mean that clinical efficacy and safety have been established across these diseases.
Barriers to clinical translation include peptide instability, potential immunogenicity, accumulation in non-target organs, and premature drug leakage. Maintaining consistent particle size and peptide loading, as well as reproducibility across manufacturing batches, also remains challenging. Assessing whether these systems can develop into actual treatments requires evaluating not only target binding but also biodistribution, immune responses with repeated dosing, and the feasibility of large-scale manufacturing.
Details of the research are available in the provided Europe PMC bibliographic record and abstract and the source of the public full-text excerpt.
The advancement of nanomedicine has significantly reshaped drug delivery strategies by overcoming key limitations of conventional pharmacotherapy, such as off-target toxicity, poor bioavailability, and adverse drug reactions (ADRs). Among emerging delivery platforms, peptide-based nanocarriers offer high biocompatibility, molecular specificity, and structural versatility for precision targeting. This review presents a comprehensive synthesis of current progress in the design, fabrication, and therapeutic application of peptide-functionalized nanocarriers for targeted drug delivery. Literature published between 2016 and 2025 was examined, with particular focus on strategies for peptide incorporation, including physical encapsulation, chemical conjugation, and self-assembly. Diverse nanocarrier platforms are discussed, including liposomes, solid lipid nanoparticles (SLNs), dendrimers, polymeric micelles, mesoporous silica nanoparticles (MSNs), and hybrid systems. Recent innovations in biodegradable polymers, co-delivery platforms, multifunctional assemblies, and stimuli-responsive formulations are highlighted. Advances in peptide design, particularly the use of cyclic and stapled peptides, have improved structural stability, target affinity, and bioavailability. Mechanistic insights into peptide-mediated targeting and physicochemical optimization are reviewed across various therapeutic contexts, including cancer, neurological disorders, infectious diseases, and inflammatory diseases. Their role in gene delivery applications, such as siRNA, mRNA, and CRISPR-Cas9 cargo delivery, is also highlighted, emphasizing the potential of peptide-functionalized systems in enabling safe and targeted nucleic acid therapeutics. Looking ahead, the development of intelligent nanocarriers capable of responding to physiological stimuli, such as pH shifts, enzymatic activity, and redox gradients, will enable spatiotemporal control of drug release. Progress in peptidomimetics and synthetic biology is expected to further enhance the therapeutic potential of peptide-based nanocarriers, ultimately leading to the creation of personalized and precision medicine approaches.
This review gives delivery-system development teams a design framework for choosing peptide roles and incorporation methods. For example, a surface peptide that recognizes a cancer-cell receptor and an element that releases a drug in response to the local environment each require functional validation. Evidence that a formulation loads a drug well or binds target cells is not, by itself, enough to establish patient benefit. To bring a candidate formulation into practical use, teams need to examine blood stability, distribution to non-target organs, and immune responses, alongside particle size, loading, and consistency between batches. Given that most approaches remain preclinical, this literature review can help prioritize follow-up experiments and manufacturing assessments rather than support treatment recommendations.