Multi-Functional Polymer Nanoparticles with Enhanced Adipocyte Uptake and Adipocytolytic Efficacy.

Multi-functional polymer nanoparticles have been widely utilized to improve cellular uptake and enhance therapeutic efficacy. In this study, we hypothesized that the cellular uptake of poly(D,L-lactide-co-glycolide) (PLG) nanoparticles loaded with calcium carbonate minerals into adipocytes could be improved by covalent modification with nona-arginine (R 9 ) peptide. We further hypothesized that the internalization mechanism of R 9 -modified PLG nanoparticles by adipocytes might be contingent on the concentration of R 9 peptide present in the nanoparticles. R 9 -modified PLG nanoparticles followed the direct penetration mechanism when the concentration of R 9 peptide in the nanoparticles reached 38 μM. Notably, macropinocytosis was the major endocytic mechanism when the R 9 peptide concentration was ≤ 26 μM. The endocytic uptake of the nanoparticles effectively generated carbon dioxide gas at an endosomal pH, resulting in significant adipocytolytic effects in vitro, which were further supported by our findings in obese mouse model induced by high-fat diet. Gas-generating PLG nanoparticles, modified with R 9 peptide, demonstrated localized reduction of adipose tissue (reduction of 13.1%) after subcutaneous injection without significant side effects. These findings highlight the potential of multi-functional polymer nanoparticles for development of effective and targeted fat reduction techniques, addressing both health and cosmetic considerations. This article is protected by copyright. All rights reserved.