Nitric Oxide‐Activated Bioorthogonal Codelivery Nanoassembly for In Situ Synthesis of Photothermal Agent for Precise and Safe Anticancer Treatment

Abstract

The development of bioorthogonal activation in drug release represents a promising avenue for precise and safe anticancer treatment. However, two significant limitations currently hinder their clinical application: i) the necessity for separate administration of the drug precursor and its corresponding activator, leading to poor drug accumulation and potential side effects; ii) the reliance on exogenous metal or organic activators for triggering bioorthogonal activation, which often exhibit low efficiency and systemic toxicity when extending to living animals. To overcome these limitations, a nitric oxide (NO)‐mediated bioorthogonal codelivery nanoassembly, termed TTB‐NH2@PArg, which comprises a precursor molecular (TTB‐NH2) and amphipathic polyarginine (PArg) is developed. In TTB‐NH2@PArg, PArg serves as both self‐assembled nanocarrier for TTB‐NH2 and a NO generator. In tumor microenvironment (TME), the TME‐specific generation of NO acts as a gas activator, triggering in situ bioorthogonal bond formation that transforms TTB‐NH2 into TTB‐AZO. This tumor‐specific generation of TTB‐AZO not only serves as a potential photothermal agent for effective tumor inhibition but also induces fluorescence change that enables real‐time monitoring of bioorthogonal activation. This study presents a drug codelivery approach that enables precise and safe control of bioorthogonal activation for anticancer treatment, improving cancer therapy efficacy while minimizing side effects.