Peptide-Based Nanocarriers for Targeted Drug Delivery: Recent Advances, Strategies, and Therapeutic Frontiers

Abstract: 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 analogues, including D-amino acids, is expanding the chemical toolkit to overcome limitations of native peptides. In parallel, the integration of artificial intelligence, machine learning, and predictive modeling tools is accelerating the rational design and optimization of peptide sequences and nanocarrier architectures. Nonetheless, clinical translation remains limited by peptide instability, potential immunogenicity, off-target effects, and the complexities of manufacturing and regulatory approval. Together, these advances establish peptide-based nanocarriers as a critical component in the next generation of personalized and precision nanomedicine. Keywords: peptide-based nanocarriers, targeted drug delivery, peptide-mediated targeting, stimuli-responsive nanomedicine, gene delivery, nucleic acid therapeutics