Nanovoid-confinement and click-activated nanoreactor for synchronous delivery of prodrug pairs and precise photodynamic therapy

Bioorthogonal cleavage reaction-triggered prodrug activation by the pretargeted methods can achieve accurate cancer therapy. However, the click and release efficiency of these methods in vivo is limited by the space-time dislocation of bioorthogonal prodrug-trigger pairs within the tumor area, caused by their asynchronous administration and inconsistent accumulation for most delivery systems. We herein created a nanovoid-confinement and click-activated (NCCA) core–shell nanoreactor by incorporating prodrugs within zeolitic imidazolate framework-90 (ZIF-90) as core and coating tetrazine-based covalent organic framework (COF) as shell. After surface modification of aptamer polymer, the NCCA nanoreactor enabled the sufficient delivery of photodynamic prodrugs within tumor. Notably, the core of ZIF-90 was decomposed by tumor acidic environment, inducing the high-efficiency activation of photodynamic prodrugs via nanoconfined bioorthogonal reaction with tetrazine-based COF shell. As a result, such photodynamic agents are efficiently and safely accumulated into tumor and specifically activated for precise photodynamic therapy of cancer cells and tumor bearing mice with minimizing toxic side effect. Taken together, such NCCA nanoreactor clearly demonstrates the critical feasibility to realize the synchronous delivery of both prodrugs and triggers for precise treatment, which most of delivery systems are not able to afford.