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 trans ‐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.