siRNA-Based\nCarrier-Free System for Synergistic Chemo/Chemodynamic/RNAi\nTherapy of Drug-Resistant Tumors

Multiple\ndrug-resistance mechanisms originate from defensive pathways\nin cancer and are associated with the unsatisfied efficacy of chemotherapy.\nThe combination of small interfering RNA (siRNA) and chemotherapeutics\nprovides a strategy for reducing drug efflux but requires more delivery\noptions for clinical translation. Herein, multidrug resistance protein\n1 (MDR1) siRNA is used as the skeleton to assemble chemotherapeutic\ncisplatin (CDDP) and divalent copper ion (Cu²⁺) for constructing\na carrier-free Cu-siMDR-CDDP system. Cu-siMDR-CDDP specifically responds\nand disassembles in the acidic tumor microenvironment (TME). The released\nCDDP activates cascade bioreactions of NADPH oxidases and superoxide\ndismutase to generate hydrogen peroxide (H₂O₂). Then a Cu²⁺-catalyzed Fenton-like reaction transforms\nH₂O₂ to hydroxyl radicals (HO^•) and causes glutathione (GSH) depletion to disrupt the redox adaptation\nmechanism of drug-resistant cancer cells. Besides, delivery of MDR1\nsiRNA is facilitated by HO^•-triggered lysosome destruction,\nthus inhibiting P-glycoprotein (P-gp) expression and CDDP efflux.\nThe unique design of Cu-siMDR-CDDP is to exploit siRNA as building\nblocks in regulating the self-assembly behavior, and integration of\nfunctional units simultaneously alleviates limitations caused by drug-resistance\nmechanisms. Such a carrier-free system shows synergistic chemo/chemodynamic/RNA\ninterference therapy in suppressing tumor growth <i>in vivo</i> and has the reference value for overcoming drug resistance.