Figure 1.

(A) Schematic illustration of the TME pH-responsive multistaged NP platform for systemic targeted siRNA delivery and effective cancer therapy. After intravenous injection (i), the siRNA-loaded NPs can extravasate from leaky tumor vasculature and accumulate in the tumor tissue (ii). In response to TME pH, the NPs rapidly disassemble to release siRNA-TCPA complexes (iii), which then target and penetrate tumor cells (iv) to achieve efficient cytosolic siRNA transport and gene silencing (v). (B) Molecular structure of TME pH-responsive polymer Meo-PEG-b-PHMEMA. (C) Molecular structure of TCPA with tumor cell-targeting and -penetrating functions attributable to the R⁸ and RGDS segments, respectively.