Enzyme-sequential responsive core-satellite nanomedicine enables activatable near-infrared-II photoacoustic imaging-guided chemotherapy cascade-enhanced radiotherapy.

The standard treatment for various types of cancers typically involves the combination of concurrent localized radiotherapy and systemic chemotherapy. However, no treatment options have been reported that utilize chemotherapy cascade-enhanced radiotherapy. In this study, we report a core-satellite nanomedicine designed to enhance radiotherapeutic effects through a cascade mechanism by triggering the release of a potent chemotherapeutic agent in response to trypsin. We synthesized a functional enzyme-sequential responsive nanomedicine, DOX@Gel-DEVD-AuNR, which consists of gelatin nanoparticles loaded with the chemotherapeutic drug doxorubicin (DOX). These nanoparticles are covalently linked to gold nanorods (AuNR) via a caspase-3 specific DEVD peptide substrate. Upon trypsin activation, the DOX@Gel-DEVD-AuNR formulation releases DOX, thereby enhancing chemotherapy efficacy against tumors. Simultaneously, it activates caspase-3, inducing the aggregation of AuNRs, which in turn activates a near-infrared-II photoacoustic signal. This signal is crucial for determining the optimal timing for X-ray irradiation. The resulting large-size AuNRs aggregates promote their accumulation within tumors by preventing the migration and backflow of AuNRs, thereby improving radiotherapeutic effects. Consequently, when combined with image-guided X-ray irradiation, DOX@Gel-DEVD-AuNR induces significant cytotoxicity in cancer cells and effectively inhibits tumor growth. Our study underscores the potential application of enzyme catalysis-mediated chemistry in activating nanomedicine for activatable image-guided chemotherapy cascade-enhanced radiotherapy.