Cytosolic supply of small interfering RNA (siRNA) stays difficult, and a profound understanding of the mobile uptake and intracellular processing of siRNA supply programs may significantly enhance the event of siRNA-based therapeutics. Right here, we present that caveolae-mediated endocytosis (CvME) accounts for the strong siRNA supply of mannose-modified trimethyl chitosan-cysteine/tripolyphosphate nanoparticles (MTC/TPP NPs) to macrophages by circumventing lysosomes. We present that the Golgi complicated and ER are key organelles required for the environment friendly supply of siRNA to macrophages through which the siRNA accumulation positively correlates with its silencing effectivity (r = zero.94). We additionally establish syntaxin6 and Niemann–Decide sort C1 (NPC1) as indispensable regulators for MTC/TPP NPs-delivered siRNA into macrophages each in vitro and in vivo. Syntaxin6 and NPC1 knockout considerably lower the mobile uptake and gene silencing of the siRNA delivered in MTC/TPP NPs in macrophages, which end in poor therapeutic outcomes for mice bearing acute hepatic harm. Our outcomes recommend that extremely environment friendly siRNA supply might be achieved through CvME, which might give concepts for designing optimum supply vectors to facilitate the scientific translation of siRNA medication.