Manganese-Doped Nanoparticles with Hypoxia-Inducible Factor 2α Inhibitor That Elicit Innate Immune Responses against von Hippel–Lindau Protein-Deficient Tumors

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

The von Hippel-Lindau (VHL) tumor suppressor gene product, pVHL, is frequently deficient in a variety of human cancers. In addressing the treatment pVHL-deficient tumors, hypoxia-inducible factor 2α (HIF-2α) has risen as promising therapeutic target, culminating development specific inhibitors like PT2385 and its analogues. Nonetheless, absence targeted delivery capabilities these heightens risk on-target toxicities. To mitigate limitations, we have engineered nanoparticle, termed PMMF (PT/MMSN@DSPE-PEG-FA), capable delivering both HIF-2α antagonist (PT2385) manganese directly to sites. shown effective targeting clear-cell renal cell carcinoma melanoma, leading significant benefits alleviating hypoxic immunosuppressive traits microenvironment. Functionally, boosts cyclic GMP-AMP synthase-stimulator interferon genes signaling pathway, which, turn, stimulates robust innate immune response. This response activates natural killer (NK) cells CD8+ T lymphocytes while curbing infiltration regulatory cells. Notably, efficacy markedly reduced when NK are blocked but not affected by neutrophil blockade, highlighting critical role PMMF-induced antitumor immunity. Additionally, safety profile showed minimal systemic post-treatment cytotoxicity. summary, our findings position platform for treating tumors with pVHL deficiency underscore potential metalloimmunotherapy.

Language: Английский

Manganese-Based Nanoadjuvants for the Synergistic Enhancement of Immune Responses in Breast Cancer Therapy via Disulfidptosis-Induced ICD and cGAS-STING Activation

Biomaterials, Journal Year: 2025, Volume and Issue: unknown, P. 123359 - 123359

Published: April 1, 2025

Language: Английский