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, it is hypothesized that the cellular uptake of poly(D,L-lactide-co-glycolide) (PLG) nanoparticles loaded with calcium carbonate minerals into adipocytes can be improved by covalent modification with nona-arginine (R9) peptide. It is further hypothesized that the internalization mechanism of R9-modified PLG nanoparticles by adipocytes may be contingent on the concentration of R9 peptide present in the nanoparticles. R9-modified PLG nanoparticles followed the direct penetration mechanism when the concentration of R9 peptide in the nanoparticles reached 38 mu M. Notably, macropinocytosis is the major endocytic mechanism when the R9 peptide concentration is <= 26 mu M. The endocytic uptake of the nanoparticles effectively generated carbon dioxide gas at an endosomal pH, resulting in significant adipocytolytic effects in vitro, which are further supported by the findings in an obese mouse model induced by high-fat diet. Gas-generating PLG nanoparticles, modified with R9 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 the development of effective and targeted fat reduction techniques, addressing both health and cosmetic considerations. The production of intracellular carbon dioxide gas from multi-functional polymer nanoparticles, modified with nona-arginine and internalized through macropinocytosis at lower peptide concentrations, efficiently initiates adipocytolysis. As a result, this process leads to a localized reduction of adipose tissue.image