Nanoreactor of “butterfly effect” inciting a triple interlocked combination of starvation/chemo/metal ion therapy by remodeling tumor microenvironment

Abstract

Tumor microenvironment has been used as the driving force of nano-therapy systems. However, due to its own complexity and heterogeneity, the therapeutic effects of many systems are still hindered by inherent cellular barriers. Herein, we designed a biodegradable nanoreactor showing interlocking “butterfly effect”, which reconstructed the tumor microenvironment (TME) by functional “butterfly” and initiated the next cascade reaction to enhance the efficacy. The silver nanocubes (Ag NCs) as the core, then loading polydopamine (PDA), glucose oxidase (GOx), and tirapazamine (TPZ), which was further disguised by tumor cytomembrane to construct as a bionic nanoreactor Ag@PDA/GOx/TPZ@M (APGTM). When the nanoreactors were homologously targeted to the tumor site, GOx as the “butterfly” caused the tumor cells entering starvation state by consuming glucose and O2 and generating gluconate and H2O2. Furtherly, the generated hypoxia state activated TPZ to achieve chemotherapy, and the non-toxic Ag NCs were degraded into toxic Ag+ under high H2O2 levels to carry out metal ions therapy. This “butterfly effect” of nanoreactor launching a triplet chain reaction can solve the problem of the lack of reciprocity on multi-modal therapy by reshaped the TME, which opens a new way for accurate and effective tumor cell ablation.