Degradable Multifunctional Porphyrin-Based Porous Organic Polymer Nanosonosensitizer for Tumor-Specific Sonodynamic, Chemo- and

Sonodynamic therapy (SDT) benefiting from its intrinsic merits, such as noninvasiveness and deep tissue penetrability, is receiving increasing considerable attention in reactive oxygen species (ROS)-based tumor treatment. However, current sonosensitizers usually suffer from low tumor lesion accumulation, insufficient ROS generation efficiency under ultra -sound, and non-biodegradability, which seriously impede the therapeutic outcomes. Additionally, it is difficult that SDT alone can completely eradicate tumors because of the complex and immunosuppressive tumor microenvironment (TME). Herein, we simultaneously employ sonosensitive porphyrin building blocks and glutathione (GSH)-responsive disulfide bonds to construct a novel degradable multifunctional porphyrin-based hollow porous organic polymer (POP) nanosonosensitizer (H-Pys-HA@M/R), which combine SDT, on-demand chemotherapy, and immunotherapy. Taking the unique advantages of POPs with designable structures and high specific surface area, this H-Pys-HA@M/R nanosonosensitizer can achieve tumor target accumulation, GSH-triggered drug release, and low-frequency ultrasound-activating ROS generation with encouraging results. Furthermore, this multifunctional nanosonosensitizer can effectively evoke immunogenic cell death (ICD) response through the combination of SDT and chemotherapy for both primary and distal tumor growth suppression. Meanwhile, H-Pys-HA@M/R exhibits favorable biodegradation and biosafety. Therefore, this study provides a new strategy for reasonably designing and constructing POP-related sonosensitizers combining SDT/chemotherapy/immunotherapy triple treatment modalities to eradicate malignant tumors.

Automated summary

Sonodynamic therapy (SDT) is a noninvasive and deep tissue penetrable treatment method that utilizes reactive oxygen species (ROS) for tumor treatment. However, current sonosensitizers face challenges such as low tumor accumulation, insufficient ROS generation, and non-biodegradability. In this study, a degradable multifunctional nanosonosensitizer was constructed using sonosensitive porphyrin building blocks and glutathione (GSH)-responsive disulfide bonds. This nanosonosensitizer achieved tumor target accumulation, GSH-triggered drug release, and low-frequency ultrasound-activated ROS generation. It also effectively induced immunogenic cell death response through the combination of SDT and chemotherapy. This study provides a new strategy for designing and constructing sonosensitizers for triple treatment modalities to eradicate tumors.