Oxygen‐Independent Photodynamic Therapy‐Mediated Selective Consumption of M1 Macrophage Against Ventricular Arrhythmias via Sympathetic Neuromodulation

Abstract The occurrence of myocardial infarction (MI)‐induced malignant ventricular arrhythmias (VAs) is closely associated with the hyperactivation of left stellate ganglion (LSG). Proinflammatory M1 macrophage is reported to aggravate sympathetic overactivation and cause VAs. Therefore, the depletion of M1 macrophage is anticipated to inhibit LSG overactivation and alleviate MI‐induced VAs. Herein, oxygen‐independent photodynamic therapy (Oi‐PDT) combined with M1 macrophage targeting is applied to selectively deplete M1 macrophage in LSG and further treat MI‐induced VAs. Oi‐PDT, which overcomes the limitation of extremely dependence on oxygen content in traditional PDT, is constructed through the generation of oxidizing photogenerated holes (h⁺) under the irradiation of near‐infrared (NIR) light on the prepared Oi‐PDT agent (PPSCD). Meanwhile, PPSCD targets M1 macrophage through conjunction with SR‐A receptor. The selective consumption of M1 macrophage is attributed to both apoptosis and ferroptosis induced by h⁺, ¹O₂, and O₂^•− generated in Oi‐PDT. In vivo tests indicated neural activity experienced a notable reduction from 104.5 ± 2.9 to 51.5 ± 6.7 after MI with Oi‐PDT treatment, thereby significantly inhibited VAs. The implementation of this study provides a promising strategy for selective consumption of M1 macrophages and treatment of VAs induced by MI.