Oral Spatiotemporal Nanoassembly for Sequential Genetic Reprogramming from Gut to Periphery Organ

Oral gene therapy for metabolic diseases necessitates physiologically aligned strategies to sequentially regulate the gut-organ axis. Nevertheless, the gastrointestinal environment and unpredictable biodistribution limit the efficiency of conventional gene delivery. Here, we develop Layer-by-Layer Chylomicron-Mimicking Self-Assembly (LbL-CMSA), which enables sequential gene reprogramming from the gut to the peripheral organs. Utilizing dynamic layer-shedding kinetics, the outer bile-salt shell peels off in enterocytes to release siRNA for local intestinal reprogramming. Subsequently, the inner lipopeptoplex layer mimics chylomicrons, entering lymphatic trafficking to bypass hepatic first-pass metabolism and deliver genes to distal metabolic organs. In an obesity model, LbL-CMSA down-regulates obesogenic genes in gut–adipose tissues by sequentially blocking intestinal fat influx and adipocyte storage. By modulating genetic cargos, LbL-CMSA attenuates endotoxin translocation across the leaky gut to amplify anti-fibrogenic effects in a steatohepatitis model. Overall, LbL-CMSA shows its potential as a modular nanoplatform for combination gene therapy to overcome complex metabolic disorders efficiently.