Sono-Triggered In Situ Vaccine via a Chlorin-Based Small Molecule Sensitizer for Systemic Cancer Therapy

Unimolecule-mediated sonodynamic therapy (SDT) offers a promising approach to combat tumors systemically by enabling synergistic sono-triggered cytotoxicity and in situ vaccine-like effects within tumors. Although chlorin-based sensitizers have achieved clinical success in phototherapy, their translation to SDT has been impeded by inadequate ultrasound (US)-triggered reactive oxygen species (ROS) generation, leading to suboptimal immunogenic cell death (ICD) and compromised antitumor immunity. To address this, we designed two organic sonosensitizers based on the natural product-derived scaffold, Chenghai pyropheophorbide-a (CHPpa). CHPpa-er was constructed by appending a p-toluenesulfonamide group for specific endoplasmic reticulum (ER) targeting. Its analogue, CHPpa-er-Asp, was additionally functionalized with aspartic acid to modulate molecular polarity. Remarkably, despite differing by only one pharmacophore, the two compounds exhibited profoundly distinct profiles in target protein (K_ATP channel) engagement and intracellular trafficking, highlighting the critical impact of rational molecular design. As the lead candidate, CHPpa-er elicited precise, intraluminal ROS bursts under US, inducing severe ER stress and robust ICD. In two preclinical tumor models, CHPpa-er-mediated SDT effectively suppressed both primary tumor growth and metastasis by provoking potent systemic antitumor immunity. This work introduced a unimolecular sonosensitizer strategy that transformed SDT from a localized modality into a systemic intervention, offering a translatable platform for comprehensive cancer therapy.