Prodrug-decorated 2D hafnium sulfide nanoplatelets as "amplify-and-arrest" platforms for radiosensitization and homologous recombinant inhibition in solid tumor.

Abstract

A two-dimensional (2D) hafnium sulfide nanoplatelet (HfNP) platform with a phospholipid coating was developed to integrate physical radiosensitization with biochemical inhibition of DNA repair through an "amplify-and-arrest" strategy. The high atomic number of hafnium gives HfNPs a large photoelectric cross-section, enhancing absorption of incident radiation and the generation of secondary electrons that amplify the locally deposited dose, with nanoparticle morphology presenting an opportunity to further increase electron escape. The lipid coating provides aqueous stability and high drug-loading capacity, enabling incorporation of a phospholipid-conjugated Mirin prodrug (proMirin) that is activated by tumor-associated pH and phospholipase A₂ to suppress homologous recombination repair. Structural characterization confirmed crystalline 2D morphology, surface coating integrity, and efficient prodrug incorporation. In vitro and in vivo studies demonstrated enhanced radiosensitization, robust inhibition of RAD51-mediated repair, prolonged intratumoral retention plausibly driven by platelet-like geometry, and minimal systemic toxicity. These results establish HfNPs as a high-Z radiosensitizing platform that improves radiotherapeutic outcomes through both enhanced physical energy deposition and biochemical blockade of damage repair, with nanoplatelet dimensionality presenting an opportunity to further strengthen these effects.