2558-P: A Versatile siRNA Delivery Platform Enabling Dual-Targeting and Multitissue Gene Silencing for Treatment of Metabolic Disorders

Introduction and Objective: Adipose tissue plays a central role in metabolism and energy balance. The first adipose-targeted siRNA, ARO-ALK7, has entered clinical development. However, obesity and metabolic diseases are multifactorial, suggesting that targeting multiple pathways across relevant tissues may improve outcomes. Here, we describe a receptor-mediated siRNA delivery platform that enables selective and tunable targeting of adipose tissue, with flexibility for dual-target and multi-tissue applications. Methods: We developed a proprietary receptor-mediated siRNA platform with high tissue selectivity. After SC administration, the platform showed robust mRNA silencing and sustained pharmacological activity in adipose tissue. Dual targeting of adipose tissue was achieved through linker engineering and ligand-conjugate optimization. Additionally, simultaneous targeting of adipose and liver tissues was enabled via optimization, allowing fine control over tissue distribution and gene silencing. Results: Adipose-selective delivery of ALK7 siRNA achieved 90% knockdown in DIO mice and 35% reduction in BW change compared to vehicle. Using this platform, a bivalent molecule was engineered using AdipoQ siRNA tool sequence. It achieved ~95% reduction in serum adiponectin for at least 2 months after single 1mpk SC injection. This approach enabled concurrent modulation of two adipose targets with significant potency and durability. A multi-tissue targeting strategy showed that simultaneous knockdown of targetX in liver and adipose resulted in greater improvements in insulin sensitivity and body weight reduction than targeting either tissue alone. Conclusion: These results establish a versatile siRNA delivery platform that enables selective, durable, and tunable gene silencing in adipose tissue, with the added capability of dual-target and multi-tissue targeting. It provides a foundation for next-generation RNAi therapeutics addressing the multifactorial nature of obesity and metabolic disease. Disclosure Z. Zi: Employee; Current; Rona therapeutics. J. Liu: None. L. Wu: None. P. Ye: Employee; Current; Rona therapeutics. J. Huang: Employee; Current; Rona therapeutics. L. Pan: Employee; Current; Rona Therapeutics. S. Shi: Employee; Current; Rona Therapeutics.