Break Conference: AIChE Annual MeetingYear: 2017Proceeding: 2017 AIChE Annual MeetingGroup: Education DivisionSession: K-12 Outreach Activities and Other Broader Impacts Time: Tuesday, October 31, 2017 - 12:55pm-1:20pm Small interfering RNA (siRNA) therapeutics have emerged as a means to post-transcriptionally silence genes and treat a wide range of genetic diseases. For clinical applications, siRNA must be encapsulated within nanoscale delivery vehicles to survive in vivo. These nanocarriers must be stable enough to deliver siRNA into targeted cells while simultaneously promoting siRNA release within these cells. Cationic polymers are a promising nanocarrier method for siRNA delivery in which the polymers electrostatically self-assemble with siRNA to form polyplex structures. However, many cationic polymer nanocarriers lack efficient siRNA delivery capabilities and controlled release mechanisms. To regulate siRNA release, our laboratories previously demonstrated the use of photo-responsive diblock copolymers to provide a method for modulating siRNA release via light-mediated charge reversal of the cationic polymer block, which breaks apart the polyplex structure and releases siRNA only upon the photo-stimulus. Herein, we explore the ability to modulate polyplex stability and gene silencing activity using mixtures of these photo-responsive diblock copolymers with two different cationic block lengths. The polymer with the shorter cationic block is shown to promote more siRNA release and form a polyplex smaller in diameter, while the polymer with the longer cationic block is shown to have increased polyplex stability and increased overall positive surface charge. By mixing the two polymers, the contradictory demand for stability and release in polyplex systems is addressed, and the polyplex diameter and surface charge are balanced to enhance uptake into cells. Through formulation of polyplexes from a 50/50 mixture of the two different diblock copolymer lengths, the level of gene knockdown easily was optimized to achieve the maximum level of 70% GAPDH protein silencing for a single dose in NIH/3T3 cells. In addition to maximizing gene silencing by tuning polymer composition, simple kinetic modeling was employed to create dosing schedules based on siRNA, mRNA, and protein concentrations in the cells over the dosing process. This modeling allowed an increase to 84% GAPDH protein silencing upon applying a second dose of polyplexes. Thus, this work demonstrates that pairing advances in biomaterial design with simple kinetic modeling provides new insight into gene silencing dynamics and a strategy for efficient tuning of polymer composition to maximally control gene silencing through polyplex siRNA delivery.