Polymeric systems for peptide and protein delivery: design principles, translational barriers, and future research directions.

Abstract

Peptides and proteins have become central to modern therapeutics because of their high biological specificity and ability to modulate targets that are often inaccessible to small molecules. However, their clinical use remains constrained by molecular instability, enzymatic degradation, rapid systemic clearance, poor epithelial permeability, immunogenicity risk, and the practical burden of repeated parenteral administration. Polymeric delivery systems offer versatile strategies to address these limitations through molecular conjugation, biodegradable depots, nanoparticles, micelles, hydrogels, nanogels, mucoadhesive systems, and microneedle-based platforms. This review summarizes the design principles, biological barriers, formulation challenges, and translational considerations that govern polymeric peptide and protein delivery. Particular emphasis is placed on polymer-cargo interactions, stability preservation, controlled release versus polymer degradation, critical quality attributes, safety, immunogenicity, manufacturability, and regulatory complexity. Clinically mature examples, including PEGylated proteins and PLGA/PLA-based long-acting depots, demonstrate that polymeric technologies can improve pharmacokinetics and dosing convenience when the delivery objective is clearly defined and product complexity remains manageable. In contrast, many nanoscale, mucosal, and stimuli-responsive systems remain limited by weak in vitro-in vivo translation, incomplete characterization of released cargo bioactivity, scale-up difficulty, and uncertain regulatory pathways. Future progress will require development strategies that begin with clinical need and target product profile rather than platform novelty alone. Successful polymeric systems are likely to be those that integrate protein stability, controlled exposure, patient usability, robust manufacturing, validated analytics, and regulatory clarity into a coherent product-development framework.