PSMA-targeted NT-PGC1α mRNA nanogels suppress prostate cancer xenograft growth by 73.4%

Prostate cancer is a leading cause of cancer-related mortality in men, with metabolic dysregulation increasingly recognized as a critical driver of disease progression. Current therapies often face challenges like resistance and systemic side effects. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a key regulator of oxidative metabolism and mitochondrial biogenesis, known to inhibit metastatic programs. Harnessing PGC1α's therapeutic potential, particularly its N-terminal isoform (NT-PGC1α), through targeted delivery of its mRNA, represents a novel strategy to metabolically reprogram cancer cells and overcome existing treatment limitations.

Researchers developed a prostate-specific, targeted disulfide-crosslinked nanogel system for intracellular delivery of mRNA encoding NT-PGC1α. These nanogels were functionalized with a peptide targeting prostate-specific membrane antigen (PSMA) to enable selective delivery to PCa cells and 3D spheroid models. The nanogels, prepared via nanopolymerization, exhibited high mRNA loading and redox-responsive cargo release, mediated by intracellular glutathione. For in vivo assessment, the PSMA-targeted NT-PGC1α mRNA-loaded nanogels were systemically administered to xenograft models, with tumor growth suppression as the primary endpoint, compared against an untreated control arm.

The targeted nanogel system achieved selective delivery of NT-PGC1α mRNA in PCa cells and 3D spheroid models, confirming sustained PGC1α expression. This led to increased mitochondrial protein content, indicative of enhanced mitochondrial biogenesis. The nanogels demonstrated low cytotoxicity and efficient cytosolic delivery following glutathione-mediated degradation. In vivo, systemic administration of the PSMA-targeted NT-PGC1α mRNA-loaded nanogels resulted in tumor-preferential accumulation. > Most importantly, the treatment led to a significant suppression of xenograft growth by 73.4% relative to the untreated control group. Furthermore, the treatment was associated with minimal systemic toxicity, highlighting its favorable safety profile in this preclinical model.