Porphyrin‐Based Covalent Organic Framework for Imaging‐Guided Cancer Combinatorial Immuno‐Sonodynamic Therapy

Abstract The rational design of tumor microenvironment (TME)‐activated nanomedicine is driving a new direction in tumor immunology. Furthermore, the novel therapeutic mode of ultrasound‐triggered sonodynamic therapy (SDT) has been proven to specifically activate the immune response. Herein, a well‐defined covalent organic framework (COF) with sonosensitive properties is synthesized through experimental and theoretical verification, followed by the efficient loading of the toll‐like receptor agonist (Poly(I:C)) and in situ growth of paramagnetic transitional metallic oxide of manganese bioxide (MnO 2 ). The MnO 2 ‐Poly(I:C)@COF shell can reverse the reductive TME by consuming glutathione (GSH) to release Mn 2+ , simultaneously generating marked magnetic resonance imaging signals for real‐time guidance. Importantly, the MnO 2 acts as an enzyme‐like nano‐catalyst to promote TME‐overexpressed hydrogen peroxide (H 2 O 2 ) and produce oxygen, facilitating SDT‐induced reactive oxygen species production, and inducing immunogenic cell death, thereby boosting immune engine and triggering abundant neoantigen exposure. With the powerful assistance of immunological agents Mn 2+ and Poly(I:C), the triggered immune engine is amplified by refueling the engine (stepping on the accelerator) to reduce the immunosuppressive state. Overall, this study improves the synthesis of multifunctional COF and expands its application. The developed nano‐sonosensitizer system provides a paradigm to enhance SDT‐based high‐performance multifunctional sonosensitizers, and this SDT‐mediated strong tumor‐suppressive efficiency and activated immune effect represent a promising combinatorial therapeutic strategy for cancer therapy.