Overcoming Biological Barriers with a Microwave-Sensitizing Nanomotor for Empowering Microwave Thermal Immunotherapy

Although heat can enhance the immunogenicity of tumors, inhomogeneous temperature distribution in deep-seated regions often leads to insufficient thermal exposure, resulting in limited antigen release and low immunogenicity. Herein, we designed microwave-sensitizing nanomotors that activate propulsion to break through biological barriers and the deep-seated delivery of heat and immune adjuvants to activate the immune response. Specifically, this nanomotor features a core of dendritic silica (DS) asymmetrically modified with bovine serum albumin-stabilized manganese dioxide nanoparticles (MnO 2 @BSA) to form the DMB structure. Subsequently, the immune adjuvant R837 and tetradecanol were loaded to obtain the final microwave-sensitizing nanomotors, DMBR. Oxygen (O 2 ) bubbles generated from the catalytic decomposition of H 2 O 2 by the heterostructured MnO 2 @BSA propel the nanomotors to actively break through these biological barriers autonomously toward deep-seated tumor cells. Furthermore, microwave irradiation accelerates the production of O 2 bubbles, enhancing the nanomotor’s movement efficiency. In vitro and in vivo studies demonstrated a 3-fold improvement of DMB. Moreover, the DMBR nanomotors promote the enhancement of heat dissemination, R837 delivery efficiency, and localized release of O 2 into deep tumor areas. Consequently, a robust immune response is triggered, as evidenced by an increased level of T cell infiltration, leading to significant suppression of both primary and distant tumors. This work presents a sequential barrier-overcoming nanomotor strategy for effective microwave thermal immunotherapy.