Polymeric Delivery Systems Advance Peptide and Protein Therapeutics by Overcoming Instability and Dosing Challenges

Peptides and proteins are vital modern therapeutics due to their high biological specificity and ability to modulate targets often inaccessible to small molecules. However, their clinical utility is hampered by inherent molecular instability, rapid enzymatic degradation, systemic clearance, poor epithelial permeability, and the practical burden of repeated injections. Current standard-of-care often involves frequent parenteral dosing, leading to compliance issues and suboptimal therapeutic outcomes. Polymeric delivery systems offer a strategic solution to these limitations, aiming to improve drug stability, control release kinetics, and reduce dosing frequency.

This review systematically summarized the design principles, biological barriers, formulation challenges, and translational considerations for polymeric peptide and protein delivery. The authors analyzed various polymeric strategies, including molecular conjugation, biodegradable depots, nanoparticles, micelles, hydrogels, and microneedle platforms. Particular emphasis was placed on understanding polymer-cargo interactions, strategies for stability preservation, the balance between controlled release and polymer degradation, critical quality attributes, safety, immunogenicity, manufacturability, and regulatory complexities across different systems.

Clinically mature polymeric systems, such as PEGylated proteins and PLGA/PLA-based long-acting depots, have successfully improved pharmacokinetics and dosing convenience. These established technologies demonstrate that clear delivery objectives and manageable product complexity are key to successful translation. For instance, PEGylation has been shown to extend half-life by reducing renal clearance and proteolytic degradation, leading to less frequent dosing for drugs like pegfilgrastim. In contrast, many nanoscale, mucosal, and stimuli-responsive systems face significant hurdles. They are often limited by weak in vitro-in vivo translation, incomplete characterization of released cargo bioactivity, and considerable scale-up difficulties. Regulatory pathways for these novel systems also remain uncertain, impeding their progress toward clinical application. The review highlights that future progress requires development strategies that prioritize clinical need and target product profiles over platform novelty alone. > Successful polymeric systems integrate robust protein stability, precise controlled exposure, patient usability, and validated analytics within a clear regulatory framework.