pH-triggered gold-PNA nanoclusters reverse miR-155-driven metabolic radioresistance in breast cancer

Radioresistance driven by metabolic reprogramming, particularly the upregulation of aerobic glycolysis, remains a critical barrier that hinders effective breast cancer treatment. MicroRNA-155 (miR-155) is a central regulator of this metabolic adaptation; however, therapeutic strategies that target miR-155 suffer from poor targeting, rapid clearance and inefficient intracellular delivery of nucleic acid inhibitors. This study presents the preparation of a pH-responsive radio-nanotherapeutic platform comprising 177 Lu-labeled, peptide nucleic acid (PNA)-based miR-155 inhibitor-functionalized gold nanoclusters that undergo pH-triggered aggregation/self-assembly in the acidic tumor microenvironment. This pH-driven in situ aggregation markedly enhances intratumoral retention and facilitates efficient cytosolic delivery of the PNA payload. Specific silencing of miR-155 suppresses glycolytic flux and lactate production, which creates a reduced glycolytic capacity that sensitizes tumor cells to radiation-triggered DNA impairment. The concurrent emission of β-particles from the 177 Lu payload delivers localized internal radiotherapy, which combines with metabolic inhibition to achieve potent inhibition of tumor growth. Leveraging this treatment-associated inflammatory response, anti-PD-L1 blockade synergizes with 177 Lu@LAuP to eradicate tumors, enhance memory T-cell formation, and maintain a favorable safety profile. This work establishes a generalizable strategy to couple stimuli-responsive nanoassembly with miRNA-directed metabolic intervention to overcome radioresistance and prime immunotherapy in solid tumors.