Polymeric nanoparticles have been widely utilized as multifunctional drug delivery systems for the treatment of various diseases, including obesity. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing calcium carbonate were fabricated by the double emulsion method as gas-generating polymer nanoparticles, and the surface of the nanoparticles were modified with a peptide containing the adipocyte-targeting sequence. Various characteristics of the PLGA nanoparticles, including size, morphology, cytotoxicity, and cellular uptake were investigated in vitro. Therapeutic efficacy of the nanoparticles was also evaluated using a high-fat diet induced obese mouse model. Adipocyte-targeting, carbon dioxide-generating PLGA nanoparticles showed a great potential for reduction of adipose tissue in vivo.