Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors
Menée in vitro et à l'aide de modèles murins de cancer primitif ou métastatique de la tête et du cou, cette étude met en évidence l'intérêt, dans le cadre d'une radiothérapie stéréotaxique ablative, de nanoagrégats d'or combinés à de petits ARN interférents ciblant la galectine 1 pour améliorer la réponse immunitaire antitumorale
Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSCgal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSCgal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSCgal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy.
Nature Biotechnology , résumé, 2024