Perfluoroalkyl Anion Strategy to Construct Anion–π+ Type NIR-II Phototheranostic Agents for Enhanced Tumor Immunotherapy via Necroptosis/Ferroptosis

Abstract Anion-π+ photosensitizers (PSs) possess exceptional reactive oxygen species (ROS) generation and precise organelle targeting that could disrupt intracellular metabolic homeostasis and induce nonapoptotic cell death, offering unique advantages in overcoming immunosuppression. However, previous reports mainly focused on modifying the π+ core but often overlooked the crucial role of anions. Herein, we present a facile perfluoroalkyl anion strategy to modulate the fluorescence intensity and ROS generation capacity of anion-π+ PSs. Perfluorobutanesulfonate (PFB) anions with a single-sided perfluoroalkyl chain and bis(perfluorobutylsulfonyl)amide (BPFB) anions bearing double-sided perfluoroalkyl chains were employed to readily replace the hexafluoroantimonate (HFA) counterions in A/HFA and TPQ/HFA, yielding A/PFB, TPQ/PFB, A/BPFB, and TPQ/BPFB. Compared to the incorporated PFB anions, the BPFB anions more effectively restrict intramolecular motion through anion-π+ and van der Waals interactions, thereby significantly enhancing the fluorescence intensity of the phototheranostic agents─by 50.8-fold and 4.2-fold in A/BPFB nanoparticles (NPs) and TPQ/BPFB NPs compared to their HFA analogues, respectively. Concurrently, TPQ/BPFB NPs with second near-infrared emission demonstrated superior ROS generation, excellent mitochondrial targeting, and remarkable resistance to photobleaching. Strikingly, TPQ/BPFB NPs can activate both necroptosis and ferroptosis under irradiation, triggering a robust systemic immune response. Additionally, the lipophilicity granted by BPFB enables TPQ/BPFB NPs to infiltrate deeper into tumors, guaranteeing a more extensive photodynamic therapy with a 95% tumor suppression rate. Crucially, the immune memory triggered by TPQ/BPFB NPs effectively decreases the occurrence of lung metastases. Altogether, the perfluoroalkyl anion strategy proposed in this study offers new insights for developing potent anion-π+ PSs.