Spatiotemporally Controlled Bioorthogonal Prodrug Activation for Precise Chemotherapy

The uncontrolled pharmacokinetics of anticancer drugs after systemic administration can cause off-target accumulation in healthy tissues, compromising the antitumor efficacy and posing serious safety issues. To address these limitations, the spatiotemporally controlled inverse electron demand Diels-Alder reaction (SC-IEDDA) strategy is developed, which controls bioorthogonal IEDDA reactions within tumor tissues for in situ prodrug activation and precise chemotherapy. The strategy employs two nanoplatforms: 1) pH-sensitive zeolitic imidazolate framework-8 (ZIF-8) nanoparticles encapsulating <i>trans</i>-cyclooctene-caged doxorubicin (TCO-DOX, the prodrug) and 2) indocyanine green (ICG)-loaded near-infrared (NIR) light-responsive nanomicelles constructed from an amphiphilic molecule comprising the tetrazine (Tz) moiety conjugated to polyethylene glycol via a thioketal (TK) linker. During systemic circulation, both nanoplatforms remain intact to prevent premature prodrug activation. Following tumor accumulation via the enhanced permeability and retention effect, the acidic environment triggers ZIF-8 degradation, locally releasing TCO-DOX. Simultaneously, NIR laser irradiation induces ICG's production of reactive oxygen species, cleaving the TK linker to liberate the Tz activator. This enables the precise triggering of bioorthogonal IEDDA reaction between TCO-DOX and Tz at the tumor site, ensuring the uncaging of doxorubicin to exert efficient antitumor efficacy. This strategy represents a critical advancement in the safe and effective application in precision oncology.