Tumor Agnostic Drug Delivery with Self-Agglomerating Nanohydrogels (SANGs)

Abstract RNA interference (RNAi) holds unique potential as a clinically viable modality to pharmacologically regulate oncogenes in sequence-specific manner. Despite its potential, systemic delivery of RNAi to tumors encounters myriad obstructions and strategies to overcome barriers have largely consisted of academic demonstrations, with few approaches reaching patients. Here, we report the development of a self-agglomerating nanohydrogel (SANGs) platform that is efficiently internalized by cancer cells, is agnostic to RNAi payload, and achieves functional suppression of multiple oncogene targets. After intravenous injection, SANGs preferentially accumulated and were retained ubiquitously in primary and metastatic loci in three aggressive cancer models in a species-agnostic manner. SANGs efficiently delivered multiple RNAi payloads that significantly suppressed oncogene expression and sensitized previously resistance tumors in vivo . SANGs were found to be safe and well tolerated in simulated clinical applications across three species. We then propose and verify a novel emergent mechanism by which SANGs achieve durable solid-tumor delivery without direct functionalization. Overall, our SANGs platform is an enabling technology for RNAi-based cancer therapeutics and is poised for advanced pharmaceutical development with multiple solid-tumor indications. One-Sentence Summary Our nanostructure achieves safe and durable tumor-agnostic delivery through a newly described environmentally-responsive mechanism.