Ultrasound-triggered carrier-free nanoprodrugs activate cGAS-STING pathway to enhance tumor-targeting chemo-immunotherapy

Chemotherapy-induced cell apoptosis results in nuclear damage and the subsequent release of double-stranded DNA (dsDNA) fragments, which can stimulate the cGAS–STING pathway to initiate antitumor immune responses. However, this pathway may be less effective due to nonspecific systemic toxicity caused by chemotherapeutic agents and inefficient dsDNA accumulation. This study aimed to develop an ultrasound (US)-triggered carrier-free nanoprodrug PBSN38-curcumin (PBSN38-CUR), incorporating the sonosensitizer curcumin (CUR) and reactive oxygen species (ROS)-responsive prodrug pinacol boronic ester-conjugated 7-ethyl-10-hydroxycamptothecin (PBSN38). The objective was to enhance tumor-targeted chemo-immunotherapy by amplifying in situ DNA damage signals to activate the cGAS–STING pathway in a microenvironment-independent manner. The biocompatible PBSN38-CUR was characterized by high drug-loading capacity, demonstrating negligible toxicity in normal tissues. PBSN38-CUR generated a significant number of ROS in tumor tissues under US irradiation. The toxic chemotherapeutic SN38 was subsequently activated to induce cellular DNA damage and eradicate solid tumors. Moreover, the released CUR led to increased ROS generation and mitochondrial damage through calcium overload, further promoting dsDNA release in the cytoplasm and amplifying a robust immunological effect by activating the cGAS–STING pathway. As a result, US-activated PBSN38-CUR significantly reduced tumor growth in a triple-negative breast cancer model, preventing lung metastases and enhancing the effectiveness of anti-PD-L1 antibody combination therapy. Overall, this study proposed a spatio-controlled strategy for activating the cGAS–STING pathway by amplifying DNA damage through US-triggered prodrug release, thereby highlighting the significant potential of this strategy for clinical translation in tumor-targeted chemo-immunotherapy. • Amplifying in situ DNA damage signals to activate the cGAS–STING pathway is essential to enhance tumor-targeted chemo-immunotherapy; • The carrier-free nanoprodrug PBSN38-curcumin (PBSN38-CUR) with high drug-loading capacity can induce cellular DNA damage only under ultrasound (US) irradiation; • US-activated PBSN38-CUR offered a spatio-controlled strategy for activating the cGAS–STING pathway in a microenvironment-independent manner.