# Spatiotemporally Controlled Bioorthogonal Prodrug Activation for Precise Chemotherapy

## TL;DR

A new strategy uses nanotechnology and light to activate chemotherapy drugs only at the tumor site, reducing side effects and improving treatment precision.

## Contribution

A spatiotemporally controlled prodrug activation strategy using bioorthogonal reactions and stimulus-responsive nanoplatforms is developed.

## Key findings

- Two nanoplatforms respond to pH and near-infrared light to release the prodrug and activator at the tumor site.
- The strategy enables in situ prodrug activation via the inverse electron demand Diels–Alder reaction for precise chemotherapy.
- This method improves antitumor efficacy while minimizing off-target effects in healthy tissues.

## Abstract

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.

A spatiotemporally controlled prodrug activation strategy is developed by integrating bioorthogonal inverse electron demand Diels–Alder reaction with stimulus‐responsive nanoplatforms. Following intravenous injection, the two nanoplatforms independently respond to low pH and near‐infrared light irradiation, releasing the prodrug and liberating the activator. This enables in situ activation of the prodrug at the tumor site for precise chemotherapy.© 2026 WILEY‐VCH GmbH