Dual-quenched and redox-responsive gold nanoplatforms for tumor-specific multimodal theranostics

Despite the immense potential of photodynamic therapy (PDT) in cancer treatment, its clinical translation remains constrained by nonspecific photosensitizer activation and limited therapeutic efficacy. Herein, we design glutathione (GSH)-responsive organic-inorganic hybrid nanoprobes (AuPPCs) featuring a dual-quenching mechanism for tumor-specific multimodal theranostics. AuPPCs utilize gold nanorods (AuNRs) as multifunctional photothermal transducers, photosensitizer quenchers, and photoacoustic signal reporters, which are modified with copper-chelated diethylenetriaminepentaacetic acid (Cu-DTPA) and pyropheophorbide-a (PPa) photosensitizers via GSH-cleavable linkers. Such a design makes the PDT efficacy of PPa quenched simultaneously by Cu-DTPA and AuNRs. The activation of AuPPCs is achieved through tumor overexpressed GSH, which can trigger disulfide cleavage to release PPa. Compared with Cu-DTPA-conjugated PPa (Cu-PPa), AuPPCs show enhanced photodynamic efficacy and fluorescence signals upon activation of GSH. On the other hand, GSH may induce Cu²⁺ reduction to generate Cu⁺, enabling the Fenton-like catalytic conversion of endogenous H₂O₂ to hydroxyl radicals (˙OH) for chemodynamic therapy (CDT). The photothermal effect of AuNRs synergistically enables photothermal therapy (PTT) and real-time photoacoustic imaging of the tumor. This triple-modality integration (PTT/PDT/CDT) achieves 83.16% tumor suppression with negligible systemic toxicity, outperforming individual therapeutic modalities. Thus, this work reports a high tumor-specific nanotheranostic platform with dual-quenched PDT efficacy for imaging-guided combination therapy.