J‐Aggregated Macrocyclic Photocatalysts Enable Nitric Oxide (NO)‐Enhanced Near‐Infrared Photocatalytic Tumor Therapy

Abstract

ABSTRACT Photocatalytic therapy (PCT) has emerged as a promising strategy for tumor therapy by disrupting mitochondrial redox homeostasis through NADH/NAD + oxidation. However, its broader application is limited by insufficient light penetration, rapid catalyst deactivation under biological conditions, and insufficient catalytic pathways under hypoxia. Here, we develop a near‐infrared (NIR)‐activated photocatalytic platform based on a donor–acceptor conjugated macrocyclic photocatalyst that enables coupled NADH oxidation and nitric oxide (NO) release. The photocatalyst self‐assembles into J‐aggregates within micellar nanostructures, enabling efficient photocatalytic NADH oxidation under 808 nm light irradiation. Simultaneous encapsulation of an N ‐nitrosamine‐based NO donor offers an oxygen‐independent electron acceptor, sustaining the photocatalytic cycle under hypoxia and enabling controlled NO release. Mechanistically, photocatalytic NADH depletion suppresses electron flux through the mitochondrial respiratory chain, while NO further impairs mitochondrial respiration, synergistically aggravating mitochondrial dysfunction and amplifying PCT efficacy. Moreover, this bioenergetic collapse downregulates heat shock protein (HSP)‐mediated stress responses, thereby sensitizing tumor cells to mild photothermal therapy (mPTT) mediated by the same J‐aggregated photocatalyst. This NO‐amplified PCT–mPTT strategy not only induces potent tumor ablation but also remodels the immunosuppressive tumor microenvironment, effectively inhibiting both primary and distant tumor growth in vivo.