Engineering human PEG10-based nanoparticles for RNA self-packaging, delivery and cancer therapy

PEG10 protein was recently uncovered to self-assemble and self-package its own mRNA into nanoparticles, but the particles require expensive transfection for production and have yet to be explored for cancer therapy. Here we develop a human PEG10-based nanoparticles (PBNPs) platform for cargo RNA self-packaging and delivery for cancer therapy. We design a process to improve the PBNPs production for 11.3-fold while reducing the cost. The PBNPs self-package mRNA of at least 7336 nucleotides and remain stable for 7 months. We engineer the PBNPs surface and tremendously improve mRNA delivery efficiencies to various cancer cells, particularly colon cancer cells (≈71%). We further reprogram the PBNPs to deliver an immunotherapeutic mRNA cocktail to colon cancer cells, which elicits T cell responses in vitro. In vivo co-administration of the engineered PBNPs and chemodrug in female mice synergizes immune responses and promotes anti-cancer efficacy, implicating the potential of PBNPs as an RNA delivery vehicle for immunotherapy. mRNA cancer therapies are limited by costly production, inefficient RNA packaging, and poor tumour targeted delivery of non-viral vectors. The authors engineer PEG10 based nanoparticles enabling efficient RNA selfpackaging, enhanced cancer targeting ( ~ 71% in colon tumours), and cytokine delivery that boosts anti-tumour immunity and improves therapeutic efficacy.