Mitochondria-targeted sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate the anti-tumor immune responses. Identifying the mechanisms underlying mitochondria-targeted SDT, further optimizing its efficacy, and developing novel sonosensitizer carriers with good biocompatibility pose major challenges to the clinical practice of SDT. In this study, we investigated the mechanisms of mitochondria-targeted SDT and demonstrated that it suppressed the mitochondrial electron transport chain (ETC) in pancreatic cancer cells through RNA-sequencing analysis. Based on these findings, we constructed the functional lipid droplets (LDs) (CPI-613/IR780@LDs), which combined mitochondria-targeted SDT with the tricarboxylic acid (TCA) cycle inhibitor CPI-613. CPI-613/IR780@LDs synergistically inhibited the TCA cycle and the ETC of mitochondrial aerobic respiration to reduce oxygen consumption and increase reactive oxygen species (ROS) generation at the tumor site, thus enhancing the efficacy of SDT in hypoxic pancreatic cancer. Moreover, the combination of mitochondria-targeted SDT and anti-PD-1 antibody exhibited excellent tumor inhibition and activated anti-tumor immune responses by increasing tumor-infiltrating CD8⁺ T cells and reducing regulatory T cells, synergistically arresting the growth of both primary and metastatic pancreatic tumors. Meanwhile, lipid droplets are cell-derived biological carriers with natural mitochondrial targeting ability and can achieve efficient hydrophobic drug loading through active phagocytosis. Therefore, the functional lipid droplet-based SDT combined with anti-PD-1 antibody holds great potential in the clinical treatment of hypoxic pancreatic cancer.

As nanomedicine-based clinical strategies have continued to develop, the possibility of combining chemotherapy and singlet oxygen-dependent photodynamic therapy (PDT) to treat pancreatic cancer (PaC) has emerged as a viable therapeutic modality. The efficacy of such an approach, however, is likely to be constrained by the mechanisms of drug release and tumor oxygen levels. In the present study, we developed an Fe(III)-complexed porous coordination network (PCN) which we then used to encapsulate PTX (PCN-Fe(III)-PTX) nanoparticles (NPs) in order to treat PaC via a combination of chemotherapy and PDT. The resultant NPs were able to release drug in response to both laser irradiation and pH changes to promote drug accumulation within tumors. Furthermore, through a Fe(III)-based Fenton-like reaction these NPs were able to convert H₂O₂ in the tumor site to O₂, thereby regulating local hypoxic conditions and enhancing the efficacy of PDT approaches. Also these NPs were suitable for use as a T₁-magnetic resonance imaging (MRI) weighted contrast agent, making them viable for monitoring therapeutic efficacy upon treatment. Our results in both cell line and animal models of PaC suggest that these NPs represent an ideal agent for mediating effective MRI-guided chemotherapy-PDT, giving them great promise for the clinical treatment of PaC.