Adaptive and Bioresponsive Peptide-Functionalized Lipid-Based Nanocarriers for Precision Nanomedicine

Abstract

Lipid-based nanocarriers have emerged as clinically validated platforms for the delivery of drugs, nucleic acids, and proteins, yet their therapeutic performance remains limited by suboptimal biodistribution, cellular uptake, cargo release, and inefficient cytosolic delivery. Peptide functionalization provides versatile strategies to overcome these limitations by combining the structural adaptability of lipid nanocarriers with the programmable functionality of peptides. This review discusses how bioresponsive peptides transform lipid-based nanocarriers from passive drug reservoirs into adaptive therapeutic systems that sense and respond to pathological cues, including dysregulated protease activity, redox imbalance, local or transient pH changes, and disease-associated receptors. We summarize established and emerging strategies for peptide integration, including post-insertion, surface conjugation, and non-covalent peptide–membrane interactions, and discuss how peptide design enables active targeting, receptor recognition, charge switching, conformational activation, and protease-triggered "stealth-to-active" transitions, with particular emphasis on protease-responsive systems. We further highlight peptide-controlled cargo release, multifunctional combination therapies, theranostic platforms, and peptide-enabled strategies to overcome the major bottleneck of endosomal escape through pH-responsive, redox-responsive, enzymatically activated, fusogenic, and coacervate-based mechanisms. Finally, we discuss key translational challenges, including peptide stability, immunogenicity, ligand-density control, scalable manufacturing, colloidal stability, and the need for predictive structure-function relationships. Collectively, peptide-functionalized lipid-based nanocarriers represent a rapidly evolving class of adaptive nanomedicines with broad potential for precision therapeutic delivery.