Nevertheless, even without a full understanding of this peptide permeation process, this approach has been adopted by Novo Nordisk to create one of the first successful oral formulations of a long, linear peptide drug (semaglutide), which is widely adopted on the market. Overall, oral peptide drug formulations are highly desirable because they offer enhanced patient compliance compared to subcutaneous injections , while also preventing potential overdose issues that can arise with subcutaneous injections for GLP-1 agonists like semaglutide, which are projected to be used by over 9% of the American population by 2030. 9 However, the development of viable oral peptide formulations has been slow due to the low proteolytic stability and poor intrinsic gastric/intestinal permeability of most peptide drugs. For example, since the 1940s, the field has been striving to develop an oral formulation of insulin, but still, no widely adopted oral formulation has been discovered. For this reason, Novo Nordisks's oral formulation of semaglutide (Rybelsus), which contains 7-14 mg of the peptide drug, co-formulated with ~400 mg of SNAC, represents a remarkable achievement in the oral peptide drug delivery space. Yet, the oral bioavailability of semaglutide with SNAC still remains very low (<1%). At the same time, the understanding of the absorption mechanism with SNAC is still very limited, which has been hindering rational, mechanistically-guided improvements to the current oral formulation of semaglutide. It is currently known that SNAC stabilizes semaglutide in the stomach by inactivating pepsin (which is achieved by increasing the local pH around the tablet ). Nevertheless, the detailed molecular mechanism by which SNAC enables semaglutide to permeate the gastric epithelial barrier remains largely unknown. Most experimental evidence suggests 20 a transcellular absorption mechanism, with one of the current theories proposing that SNAC fluidizes the membrane, which then assists semaglutide in passing through the gastric epithelial cells. Although initial computational studies have provided valuable insights into the interactions between SNAC and model membranes, no detailed molecular mechanism for semaglutide permeation has yet been verified. Specifically, it remains unclear how membrane fluidization can facilitate peptide permeation without damaging the epithelial cells. Here, we now describe a viable molecular mechanism for SNAC-enabled peptide permeation of semaglutide. Our results were obtained with accurate, all-atom CpHMD simulations and are supported by experimental evidence obtained in CDCl3 as a well-established model for the hydrophobic membrane interior. Notably, in our μs-long CpHMD simulations, we observed semaglutide spontaneously incorporating into the membrane in the presence of the permeation enhancer SNAC, which explains, for the first time, how a long linear, and relatively polar peptide can get past the phospholipid barrier in a membrane in the presence of a permeation enhancer without damaging the integrity of the membrane.