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 (MnO2). The MnO2‐Poly(I:C)@COF shell can reverse the reductive TME by consuming glutathione (GSH) to release Mn2+, simultaneously generating marked magnetic resonance imaging signals for real‐time guidance. Importantly, the MnO2 acts as an enzyme‐like nano‐catalyst to promote TME‐overexpressed hydrogen peroxide (H2O2) 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 Mn2+ 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.

An iodide-containing covalent organic framework for enhanced radiotherapy

“…Covalent organic frameworks (COFs), which are crystalline porous polymeric materials with well-dened chemical structures, [25][26][27][28][29][30] have attracted extensive research interest in the tumor nanomedicine eld, and have been used in drug delivery, [31][32][33][34][35][36] phototherapy, [37][38][39][40][41][42][43][44][45][46] and immunotherapy [47][48][49][50][51][52] because they are versatile and biocompatible. Recently, AgI@COF-TpBpy was used as a delivery vehicle for radioiodine in brachytherapy, showing a long tumor retention time and effective cancer cell killing performance; 53 however, to our knowledge, the potential of a metal-free COF itself as a radiosensitizer in radiotherapy has not been exploited.…”

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

“…Hypoxia is a major contributor to radio-resistance. Thus, tumor re-oxygenation strategies, including the use of oxygen-saturated nanomaterials (perfluorocarbon), 115 oxygen-generators (MnO 2 ), 116 NO-releasing prodrugs, 117 HIF-1α inhibitor-containing carriers, 118 catalase, catalase-like metals or H 2 O 2 , 119 have been employed to address tumor hypoxia-induced radioresistance. iii.…”

“…MnO 2 nanomedicine-mediated immunomodulation and radiosensitization have been discovered to some extent: Mn 2+ augments the STING signaling and hypoxia-mediated radioresistance is relieved by oxygen generation in a MnO 2 -mimic catalyst decomposition of over-expressing H 2 O 2 in TME. 116…”

Targeting Tumor Microenvironment by Metal Peroxide Nanoparticles in Cancer Therapy

“…Researchers have shown that the Fenton reaction can cause oxidative damage to the cancer cells' DNA, proteins, or lipids, which can be targeted for treatment [118]. Te right conditions are created for the Fenton reaction (Fe 2+ + H 2 O 2 ⟶ Fe3 + + •OH + OH−) to take place by the overexpression of H 2 O 2 (100 M) and moderate acidity of TME [119].…”