Dual-Locked Nanophotosensitizer Harnessing Cerenkov Radiation for Deep Tumor Therapy

Photodynamic therapy (PDT) faces significant challenges in treating deep tumors due to the limited light penetration depth. Cerenkov radiation-induced PDT (CR-PDT) offers a potential solution by harnessing luminescence derived from radionuclides. However, the simultaneous delivery of radionuclides and photosensitizers in conventional CR-PDT systems leads to unnecessary phototoxicity of healthy tissues. Here, we present a tumor microenvironment (TME)-activated, dual-locked nanophotosensitizer (⁸⁹Zr-PHZ-BrCyE) that integrates ⁸⁹Zr-labeled pH-responsive polymeric micelle and a carboxylesterase (CrES)-activated photosensitizer prodrug for precise deep tumor therapy. The dual-responsive CR-PDT system demonstrated highly selective cytotoxicity toward hepatocellular carcinoma (HepG2) cells, with minimal impact on normal liver cells (L02). Upon intravenous injection, ⁸⁹Zr-PHZ-BrCyE exhibited robust tumor inhibition and excellent biosafety in both subcutaneous and orthotopic H22 tumor models. This approach holds great promise for improving the therapeutic outcomes of CR-PDT in deep-seated tumors while ensuring good biosafety, paving the way for future potential clinical applications in the future.