A Novel Tumor‐Penetrating Phosphorescent Nanoagent for Hypoxia‐Activated NIR‐II Bioimaging and Type‐I PDT‐Triggered Ferroptosis

ABSTRACT Controllable photodynamic therapy (PDT)‐triggered ferroptosis is a highly effective precisely controlled tumor therapy. However, conventional “always‐on” type‐I PDT agents suffer from poor tumor specificity, limiting therapeutic precision. Herein, a novel tumor‐penetrating phosphorescent nanoagent (iRGD‐mediated organometallic complex nanoparticles, iPNs) was developed for hypoxia‐activated near‐infrared‐II (NIR‐II) “turn‐on” bioimaging and type‐I PDT. The prominent intersystem crossing (ISC) property of the organometallic complex (PdTCPP) facilitated both hypoxia‐activated NIR‐II phosphorescence and efficient type‐I PDT in iPNs. Moreover, conjugation with the iRGD peptide enhanced the tumor penetration of the nanoagent. The hypoxia‐activated NIR‐II phosphorescence of iPNs, combined with their enhanced tumor penetration capability, resulted in a 5‐fold higher tumor‐to‐normal tissue (T/NT) ratio than that induced by conventional NIR‐II probes. This significantly improved tumor specificity. Subsequently, iPNs‐triggered type‐I PDT significantly promoted the intracellular accumulation of superoxide anion radicals (O 2 •− ) and hydroxyl radicals (·OH) in cancer cells, thereby inhibiting tumor growth. Proteomic analysis of both cells and tumor tissues further revealed the key ferroptosis and apoptosis pathways. Overall, this study demonstrates that the organometallic complex nanoagent with hypoxia‐activated NIR‐II bioimaging capability has the potential to guide precision type‐I PDT to induce ferroptosis.