Mimicking the osteosarcoma surfaceome on nanoparticles for targeted gene therapy.

This study developed biomimetic nanoparticles by coating poly(lactic-co-glycolic acid) (PLGA) nanoparticles with membranes derived from osteosarcoma cells, forming cell membrane-coated nanoparticles (CMCNPs). The CMCNPs showed specific binding to their source cancer cells (homotypic targeting) while evading detection by macrophages and degradation in lysosomes. The stealth property of CMCNPs was demonstrated by reduced protein adsorption and minimal liver retention in vivo. The work highlights the role of Disabled Homolog-2 (Dab2) in mediating the internalization of CMCNPs. Through mass spectrometry based label-free quantitative proteomics and inhibitor studies, this study reveals the contribution of Dab2 to enhancing the cytosolic delivery of nanoparticles. Building on this mechanistic insight, the therapeutic potential of CMCNPs was evaluated by encapsulating an siRNA payload targeting the oncogenic mRNA survivin. The release of siRNA from the nanoparticles demonstrated significant tumor penetration and regression activity, with no off-target effects observed on major organs in vivo, enabling precise survivin gene targeting with enhanced specificity and therapeutic efficacy for osteosarcoma management.