Zwitterion‐Coated Virus‐Like Nanoparticles Enable Oral siRNA Delivery for Tumor Autophagy and Immune Activation

Abstract Oral delivery of nucleic acid therapeutics for cancer therapy encounters major challenges, such as gastrointestinal acidity, enzymatic degradation, mucus barriers, and P‐glycoprotein (P‐gp) efflux. To address these challenges, this study engineers virus‐like nanoparticles encapsulating siCENPN nucleic acid complexes and irradiated tumor cells (ITC), further coated with zwitterionic bacterial cellulose derivatives (PB‐BC‐BY). This innovative formulation demonstrates enhanced mucus penetration, improves stability in gastrointestinal environments, and effective inhibition of P‐gp‐mediated efflux. The nanoparticles effectively deliver siRNA into tumor cells, resulting in marked downregulation of CENPN expression and strong autophagy induction. The autophagic tumor cells and ITCs subsequently stimulated peripheral blood mononuclear cells (PBMCs) to secrete anti‐tumor cytokines, thereby triggering an immune response. In vivo experiments confirm that orally administered nanoparticles successfully traverse the gastrointestinal barrier, enter systemic circulation, target tumors, and significantly inhibit tumor growth. Enhanced activation of dendritic cells, along with increased infiltration of cytotoxic T lymphocytes (CTLs) and Th1 cells in the tumor microenvironment, further confirms effective immune activation. Moreover, this treatment induces strong immune memory, prolonges survival, and provides substantial protection against tumor recurrence. This study presents a novel oral delivery strategy for nucleic acid therapeutics, offering an effective approach by simultaneously inducing tumor cell autophagy and promoting a robust immune‐mediated anti‐cancer response.