Mimicking the Osteosarcoma Surfaceome on Nanoparticles for Targeted Gene Therapy

Abstract

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). Using a co-extrusion method, the coating was achieved with high efficiency, both qualitatively and quantitatively. These CMCNPs showed specific binding to their source cancer cells (homotypic targeting), while also evading detection by macrophages and degradation in lysosomes. Their stealth properties were further confirmed by reduced protein adsorption and minimal liver retention. Although Clathrin-mediated endocytosis (CME) is a known pathway for nanoparticle uptake, the detailed connection to internalization remain unclear. Most studies generalize CME without identifying key adaptor proteins involved. This work highlights the role of Disabled Homolog-2 (Dab2), an adaptor protein in CME, in mediating the internalization of CMCNPs. Through label-free quantification mass spectrometry and inhibitor studies, the study reveals Dab2 contribution to enhancing cytosolic delivery of nanoparticles. To evaluate the therapeutic efficacy of a payload within CMCNPs, a siRNA molecule targeting the oncogenic mRNA survivin was encapsulated, resulting in siRNAsur-CMCNPs. 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 heightened specificity and therapeutic efficacy.