One-pot modular nanogel platform utilizing phenolic gelatin-polyethyleneimine for small RNA delivery

초록

With the vast potential of RNA drugs widely recognized, nanoparticles have emerged as a promising tool for their bench-to-bedside translation in a broad range of clinical settings. However, despite the development of thousands of polymers for small RNA (sRNA) delivery, their clinical translatability remains limited. Here, we describe a modular nanogel platform, sRNA-moduGels, that can be administered immediately after simple, one-pot preparation within 5 mins, regardless of expertise or specialized equipment. sRNA-moduGels were prepared through high-shear granulation of RNA/polymer agglomerates, induced by agitated fluid mixing and electrostatic interactions between sRNA and the cross-linkable precursor material, phenolic gelatin-branched polyethyleneimine (phGel-PEI). The resulting sRNA-moduGels were characterized for size, surface charge, loading efficiency, stability, release profile, and resistance to RNase degradation. Extensive in vitro evaluations, including cytotoxicity, intracellular uptake, and gene silencing efficacy, were conducted across various dosages, cell types, and mi/siRNAs. Additionally, organ-specific distribution and safety were also assessed in vivo. This study provides proof of concept for the flexible application of sRNA-moduGels as an RNA delivery platform and potentially serves as a prototype for advancing the translation of RNA discoveries, broadening their applicability through further engineering of ready-to-use nanogel materials.

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