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.