Tailored virus-mimicking nanoparticles mediate high transfection of pTRAIL for bystander effects in oncotherapy

Viral vectors share unparalleled gene-transfection efficiency due to protein capsid-mediated target-cell recognition and efficient cellular translocation, but clinical applications are seriously hampered by potential biosafety issues. Herein, we develop a virus-mimicking nanoparticle to enable safe, selective, and efficient TRAIL-expressing plasmid (pTRAIL) transfection for site-specific apoptosis and bystander effects. For preparation, a reactive oxygen species (ROS)-responsive phenylboronic acid-rich quaternized polymer (CRP) is synthesized for electrostatic compression of pTRAIL and coordinative coupling for apolipoprotein A-I with iRGD peptide conjugation, which is termed as iaCRP/pTRAIL nanoparticles with "gene core-protein shell" structure. The tailored virus-mimicking nanoparticles could prevent pTRAIL payloads from serum elimination, accompanied by site-specific accumulation and penetration. After cellular internalization, ROS-triggered nanoparticles disassembly could further perform burst pTRAIL release and high TRAIL expression. Our findings confirm TRAIL-derived apoptosis and bystander effects, giving <i>in vivo</i> tumor inhibition of ∼80 % and metastasis suppression of over 90 %. Collectively, the virus-mimicking strategy provides novel insights into bionic gene delivery and transfection design for efficient and safe oncotherapy.