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.