Mohammadmahdi Eshaghi, Marzieh Dehghani, Azam Abedi, Mehrdad Moosazadeh Moghaddam, Ramezan Ali Taheri
Background and purpose: Therapeutic peptides offer high potency but are limited by rapid degradation, poor bioavailability, and the need for frequent dosing. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles and microparticles are effective carriers that protect peptides and enable controlled release. This review summarizes the mechanisms governing peptide release from PLGA particles and identifies formulation factors critical for optimizing therapeutic performance. Approach: A comprehensive analysis of polymer characteristics, particle design parameters, peptide physicochemical properties, and formulation strategies was conducted using data from recent studies. Release mechanisms, including diffusion, polymer degradation, and erosion, were examined alongside manufacturing methods. The review also evaluates clinical PLGA-based peptide products to highlight translational relevance. Key results: Peptide release profiles are strongly influenced by PLGA molecular weight, lactide:glycolide ratio, particle size, end-group chemistry, drug loading, and excipients. Lower polymer molecular weight, higher glycolide content, and smaller particle dimensions accelerate release, whereas cationic peptides experience electrostatic retention within degrading matrices. Additives such as PEG, magnesium salts, and chitosan coatings effectively modulate burst release and stability. PLGA systems typically display triphasic release profiles governed by diffusion and erosion. Several PLGA microparticle-based peptide depots have achieved clinical success, although no nanoparticle-based products have yet reached the market due to manufacturing and regulatory challenges. Conclusion: PLGA nano- and microparticles provide versatile, tunable platforms for sustained peptide delivery. Understanding the interplay between polymer properties, particle architecture, and peptide characteristics is essential for designing next-generation long-acting formulations with improved efficacy and clinical translation.