A TNBC-Targeting Nano-Radiosensitizer Reverses Radioresistance by Synergizing GSH Scavenging with Dual Inhibition of Trop2 and lncRNA MNX1-AS1

Radioresistance in triple-negative breast cancer (TNBC) frequently results in local recurrence and distant metastasis, seriously affecting the prognosis of patients. The increased generation of cellular glutathione (GSH) and the upregulation of pro-malignant molecules are two major causes of radioresistance in TNBC, which need to be comprehensively considered in treatment. Herein, a TNBC-targeted reduction-responsive RNA interference (RNAi) nano-radiosensitizer (TREARA) was developed to reverse radioresistance by synergizing GSH depletion with combined inhibition of two promising pro-malignant molecules, Trophoblast cell surface antigen 2 (Trop2) and lncRNA Motor neuron and pancreas homeobox 1–antisense RNA1 (lncMNX1-AS1). Once arriving at the tumor sites with the prolonged circulation maintained by PEGylation, TREARA was rapidly internalized by tumor cells and blocked the Trop2-dominant pro-metastatic signaling through the anti-Trop2 antibody (αTrop2) modified on its surface. Subsequently, in response to the highly concentrated GSH in the cytoplasm, the shell of TREARA containing poly(disulfide amide) polymer (PDSA) was broken, unlashing the loaded lncMNX1-AS1 siRNA (siMNX1-AS1), which would suppress tumor progression by inactivating JAK3/STAT3 signaling. Benefiting from the integration of GSH-scavenging and dual-targeted inhibition of Trop2 and lncMNX1-AS1, TREARA significantly reversed radioresistance and restrained metastasis in murine models. Taken together, TREARA provides a promising comprehensive perspective for refractory radioresistant TNBC treatment.