Tumor microenvironment-responsive DNA-based nanomedicine triggers innate sensing for enhanced immunotherapy.

Lack of proper innate sensing inside the tumor microenvironment could reduce both innate and adaptive immunity, which remains a critical cause of immunotherapy failure in various tumor treatments. Double-stranded DNA (dsDNA) has been evidenced to be a promising immunostimulatory agent to induce type I interferons (IFN-Is) production for innate immunity activation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, yet the unsatisfactory delivery and susceptibility to nuclease degradation hindered its feasibility for further clinical applications. Herein, we report on the constructed tumor microenvironment-responsive DNA-based nanomedicine loaded by dendritic mesoporous organosilica nanoparticles (DMONs), which provide efficient delivery of dsDNA to induce intratumoral IFN-Is production for triggering innate sensing for enhanced anti-tumor immunotherapy. Extensive in vitro and in vivo evaluations have demonstrated the dramatic IFN-Is production induced by dsDNA@DMONs in both immune cells and tumor cells, which facilitates dendritic cells (DCs) maturation and T cells activation for eliciting the potent innate immune and adaptive immune responses. Desirable biosafety and marked therapeutic efficacy with a tumor growth inhibition (TGI) of 51.0% on the murine B16-F10 melanoma model were achieved by the single agent dsDNA@DMONs. Moreover, dsDNA@DMONs combined with anti-PD-L1 antibody further enhanced the anti-tumor efficacy and led to almost complete tumor regression. Therefore, this work highlighted the immunostimulatory DNA-based nanomedicine as a promising strategy for overcoming the resistance to immunotherapy, by promoting the IFN-Is production for innate immunity activation and remodeling the tumor microenvironment.