Enantioselective Induction of Immunogenic Cell Death: A Type-I Photodynamic Therapy Enabled by Chiral Porphyrin/Arginine Self-Assemblies

The development of chiral type-I photosensitizers represents a significant advance, as it can not only overcome the hypoxia limitation inherent to conventional type-II agents but also leverage enantioselectivity to enhance therapeutic precision. However, this promising field remains notably underexplored. Herein, we construct chiral supramolecular self-assemblies via hydrogen-bonding interactions between l/d-arginine (l/d-Arg) and 5,10,15,20-tetrakis(4-sulfophenyl)porphyrin (TPPS). The proximity of the electron-donating porphyrin core to the arginine moiety facilitates efficient photoinduced electron transfer, enabling l/d-Arg-TPPS to operate via simultaneous type-I and type-II pathways. This dual mechanism ensures robust generation of superoxide radicals (O2•–) even under hypoxic conditions, addressing a key limitation of conventional porphyrin photosensitizers. Moreover, the self-assembly process drives effective supramolecular chirality induction, endowing TPPS with substantial dissymmetry factors (gabs) of ∼2.1 × 10–4. This chiral signature translates to significant biological enantioselectivity. d-Arg-TPPS achieves 3.87-fold greater cellular uptake and 1.85-fold higher intracellular reactive oxygen species (ROS) production than l-Arg-TPPS, resulting in markedly enhanced chirality-specific antitumor activity. Importantly, l/d-Arg-TPPS also elicits a chirality-dependent immunogenic cell death (ICD) response, facilitating antitumor immunity. This work establishes a supramolecular chiral-engineering strategy that integrates hypoxia-tolerant photodynamic behavior with stereoselective nanobio interactions, advancing both the fundamental understanding and therapeutic potential of photosensitizer design.