Immune-Evasive NIR-II Nanoplatforms for Repeatable Photodynamic Therapy

Photodynamic therapy (PDT) offers the distinctive advantage of repeatable treatment without cumulative systemic toxicity. However, clinical translation is hindered by oxygen dependency, photothermal leakage, and immune clearance during multiple administrations. Here we report a next-generation photodynamic nanoplatform (<b>KD1</b>-loaded hyaluronic acid-poly(ethylene glycol) nanoparticles, <b>KD1@HPEG</b> NPs), an immune-evasive near-infrared II (NIR-II) photodynamic nanoplatform that integrates Type I photochemistry, deep-tissue fluorescence imaging, and stealth surface engineering to sustainable and precise PDT. The thiopyrylium photosensitizer <b>KD1</b> incorporates a rigid electron-donating substituent that induces pronounced orbital reconfiguration, thereby enhancing intersystem crossing while suppressing nonradiative decay. This design enables efficient type I reactive oxygen species generation with negligible heat release. <b>KD1@HPEG</b> NPs further improve the stability of <b>KD1</b>, prevent anti-PEG antibody formation to circumvent the accelerated blood clearance effect, and impart intrinsic tumor affinity. These molecular and immunological optimizations support oxygen-independent ROS generation, sustained NIR-II imaging, and preserved therapeutic efficacy under repeated dosing. <b>KD1@HPEG</b> NPs establish a generalizable strategy for long-term, immune-tolerant PDT and offers a clinically viable platform for durable, precision phototheranostics.