The Genesis Framework: A Systems-Control Architecture for Safe Partial Cellular Rejuvenation via Stoichiometric saRNA Delivery, Integrated miRNA Logic Gating, and SORT Lipid Nanoparticles

Abstract

Biological aging is increasingly understood as a process of reversible epigenetic regulatory drift rather than irreversible structural deterioration. The Genesis Framework proposes a systems-control architecture for safe partial cellular rejuvenation, grounded in four interdependent regulatory principles: stoichiometric transcriptional control of OCT4, SOX2, and KLF4 at a 3:2:1 molar ratio to promote chromatin remodeling without pluripotency induction; transient self-amplifying RNA delivery via 72-hour pulse using non-integrating saRNA; a microRNA-based dual-gate safety architecture utilizing the Let-7 and miR-294 axis within the 3' UTR to ensure biological activity exclusively in mature somatic cells; and tissue-network coordination through GDF11 and TIMP2 paracrine signaling. Delivery is proposed via selective organ targeting SORT lipid nanoparticles incorporating DOTAP at 5 mol% with m1-Psi-modified saRNA for nuclease resistance. All framework parameters emerged from 21,000 dual-validation simulation cycles concurrently testing efficacy and safety using BioNetGen, Python, and AlphaFold 3 integrated with Human Cell Atlas stochastic noise parameters. Experimental validation is outlined using human dermal fibroblasts as a primary model with falsifiable predictions anchored to Horvath DNA methylation clock reversal and NANOG suppression as primary endpoints. This document is a theoretical framework and complete laboratory blueprint released under CC0 for unrestricted scientific replication by independent biological laboratories worldwide.