Cell-Penetrating Peptides and Nanoparticle-Based Hybrid Delivery Systems: Design, Mechanisms and Therapeutic Applications

Abstract

Cell-penetrating peptides (CPPs) and nanoparticles have emerged as pivotal tools in advancing modern drug delivery, enabling the efficient transport of therapeutic molecules across biological barriers. This paper reviews the design principles, classifications, uptake mechanisms and conjugation strategies of CPPs and explores their integration with diverse nanoparticle systems. CPPs, short amino acid sequences capable of crossing cell membranes, enhance intracellular delivery, while nanoparticles offer protection, controlled release and targeting capabilities. Together, CPP–nanoparticle hybrids enable applications in drug delivery, gene therapy, diagnostic imaging and antimicrobial therapy. We discuss uptake pathways, structural modifications, endosomal escape strategies and bioconjugation methods (covalent and non-covalent) and highlight therapeutic examples including SPIONs, gold nanoparticles, quantum dots, polymeric and lipid carriers. Preclinical and clinical studies demonstrate encouraging results, with some CPP-based candidates reaching advanced trial stages. Despite challenges of stability, selectivity and systemic clearance, advances such as activatable CPPs (ACPPs) and optimized conjugates offer promising avenues. These hybrid systems represent a critical step toward precision medicine and the treatment of complex diseases.