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Clinical applications using this bioactive are, however, hindered by systemic toxicity due to the high doses used, increasing costs and reducing patient adherence. The use of a controlled-release polymeric nanoparticulate system that can potentially decrease the administered dose, and therefore the associated costs, may additionally improve overall patient acceptability without affecting therapeutic efficacy. This study provides for the development, statistical optimization and characterization of poly(lactic-co-glycolic acid) nanoparticles (PLGANPs) for the controlled release of IFN\u03b1. A double-emulsion solvent evaporation method was employed for nanoparticle (NP) synthesis, with formulation optimization achieved through a Central Composite Design (CCD) approach to ensure adequate size, stability, and sustained release over five days. Characterization of the optimized IFN\u03b1-PLGANPs using dynamic light scattering, zeta potential analysis, scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and drug release studies at pH 7.2 displayed an average particle size of 97.03\u00a0nm (PDI\u2009=\u20090.182), zeta potential of\u2009\u2212\u200934.10\u00a0mV and a maximum drug release of 5\u00a0days, with morphological analysis revealing the formation of spherical NPs with a smooth surface topology, confirming the homogeneity and structural stability of the formulation. These findings underscore the potential of the developed PLGANPs as a suitable platform for the controlled release of IFN\u03b1, noting the use of advanced nanotechnology-driven solutions to overcome the limitations of conventional therapies.<\/jats:p>","DOI":"10.1208\/s12249-026-03548-7","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:05:56Z","timestamp":1790705156000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Optimization of PEG-PLGA Immunotherapeutic Nanoparticles for the Controlled Release of IFN\u03b1"],"prefix":"10.1208","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5039-7006","authenticated-orcid":false,"given":"Magdi E. 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