Dual-Powered Nanomotor In Situ Vaccine with Tumor-Confined Penetration and Acidity Neutralization Boosts Stimulator of Interferon Genes-Mediated Immunotherapy.

Abstract

Despite its great potential, the clinical outcome of an in situ vaccine (ISV) remains limited due to inadequate immune activation within the tumor microenvironment (TME). This limitation is largely attributed to the dense tumor matrix and the immunosuppressive acidic condition that respectively, impede intratumoral drug diffusion and dampen immune responses. Herein, we construct a dual-powered nanomotor ISV by synthesizing PEGylated spindle-shaped MnCO₃ nanoparticles loaded with stimulator of interferon genes (STING) agonist cGAMP (MnCO₃-P@cGAMP) to simultaneously tackle these physical and biochemical barriers. This ISV system can produce CO₂ and O₂ gas in response to H⁺ and H₂O₂ in TME, respectively, leading to catalytic and decomposition reactions with dual-powered autonomous motion, which in turn results in robust propulsion to deeply penetrate tumors. Importantly, the penetration behavior is precisely confined in tumors only, without impacting the tumor-containing normal tissue with lower H⁺ and H₂O₂ levels. Furthermore, this nanomotor ISV effectively neutralizes the tumor acidity and coreleases Mn²⁺ and cGAMP that cooperatively trigger STING signaling, thereby reprogramming tumor-associated macrophages and enhancing cytotoxic T cells infiltration, leading to excellent systemic antitumor immunity in combination with anti-PD-L1 antibodies in multiple tumor models. This work would potentially shift the current ISV design by introducing nanomaterials with tumor-specific autonomy.