Activatable "Matryoshka" nanosystem delivery NgBR siRNA and control drug release for stepwise therapy and evaluate drug resistance cancer.

Drug resistance is always a challenge in conquering breast cancer clinically. Recognition of drug resistance and enhancing the sensitivity of the tumor to chemotherapy is urgent. Herein, a dual-responsive multi-function "Matryoshka" nanosystem is designed, it activates in the tumor microenvironment, decomposes layer by layer, and release gene and drug in sequence. The cell is re-educated by NgBR siRNA first to regain the chemosensitivity through regulating the Akt pathway and inhibit ERα activation, then the drugs loaded in the core are controlled released to killing cells. Carbonized polymer dots are loaded into the nanosystem as an efficient bioimaging probe, due to the GE11 modification, the nanosystem can be a seeker to recognize and evaluate drug-resistance tumors by photoacoustic imaging. In the tumor-bearing mouse, the novel nanosystem firstly enhances the sensitivity to chemotherapy by knockdown NgBR, inducing a much higher reduction in NgBR up to 52.09%, then effectively inhibiting tumor growth by chemotherapy, tumor growth in nude mouse was inhibited by 70.22%. The nanosystem also can inhibit metastasis, prolong survival time, and evaluate tumor drug resistance by real-time imaging. Overall, based on regulating the key molecules of drug resistance, we created visualization nanotechnology and formatted new comprehensive plans with high bio-safety for tumor diagnosis and treatment, providing a personalized strategy to overcome drug resistance clinically.