A resveratrol dimer nanoagent boosts sonodynamic-immunotherapy via suprathreshold autophagy.

Suprathreshold autophagy (SA)-induced immunogenic cell death (ICD) has emerged as a promising strategy in cancer immunotherapy. The reactive oxygen species (ROS) storm from sonodynamic therapy (SDT) has garnered significant attention due to its potential to enhance autophagy. However, the ability to modulate autophagy is still hindered due to insufficient and transient ROS generation, thereby weakening the ICD response. Therefore, disrupting the intracellular autophagic threshold is critical for amplifying the immunotherapeutic effects of SDT. Here, a ROS-responsive resveratrol (Res) dimer (Res-TK-Res, RTR) is synthesized by thioketal (TK) as a cleavable linker to endow precise drug release of the autophagy inducer. Driven by precise weak interaction-mediated supramolecular recognition, the guest molecules Chlorin e6 (Ce6) and RTR associate with the host molecule phospholipid (PC) to obtain a PC-based inclusion complex by co-solvent method. After that, a stable nanoagent is constructed by the above PC-based inclusion complex based on the self-assembly strategy. It is found that this nanoagent, with outstanding stability and favorable biocompatibility, can achieve the precise release of Res and Ce6 at tumor sites under the stimuli of tumor-endogenous ROS, induce SA during SDT, promote ICD, and enhance the antitumor immune response. Notably, the nanoagent can remarkably upregulate LC3B expression to trigger SA, thereby exerting significant antitumor efficacy in vivo in a mouse breast cancer model. Importantly, this nanoagent can not only address various limitations of SDT in modulating autophagy but also provide a novel metastatic cancer immunotherapy based on SDT and SA-induced ICD.