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.

Though imaging-guided multimodal therapy has been demonstrated as an effective strategy to improve cancer diagnosis and therapy, challenge remains as to simplify the sophisticated synthesis procedure for the corresponding nanoagents. Herein, an in-situ one-step reduction-encapsulated method has been reported, for the first time, to synthesize multicore-shell polydopamine-coated Ag nanoparticles (AgNPs@PDA) as a cancer theranostic agent, integrating amplified photoacoustic imaging, enhanced photothermal therapy, and photothermal promoted dual tumor microenvironment-coactivated chemodynamic therapy. The photoacoustic signal and the photothermal conversion efficiency of AgNPs@PDA nanosystem present a 6.6- and 4.2-fold enhancement compared to those of M-AgNPs-PDA (simply mixing PDA and AgNPs) derived from the increased interface heat transfer coefficient and the stronger near-infrared absorption. Importantly, AgNPs@PDA coactivated by dual tumor microenvironment (TME) enables controllable long-term release of hydroxyl radicals (·OH) and toxic Ag⁺, which can be further promoted by near-infrared light irradiation. Moreover, the high efficiency of AgNPs@PDA nanosystem with prominent photoacoustic imaging-guided synergistic photothermal-chemodynamic cancer treatment is also found in in vitro and in vivo studies. As a special mention, the formation mechanism of the one-step synthesized multicore-shell nanomaterials is systematically investigated. This work provides a much simplified one-step synthesis method for the construction of a versatile nanoplatform for cancer theranostics with high efficacy.