Omniphilic polysaccharide-based nanocarriers for effective delivery in alternating environments. Side chain engineering strategy to manipulate properties and activity

Self-adjusting omniphilic nanocarriers (OPNs) with a multi-solvent aptitude were prepared via a Schiff base reaction between chitosan, a natural polysaccharide, and bioactive aldehydes. Experimental studies supported by atomistic molecular dynamics simulations revealed these OPNs can encapsulate insoluble molecular cargo, transport them in aqueous or lipid environments, and deliver them through cross-phase barriers. N-imine dynamic covalent bonds have been incorporated to endow the OPNs with pH responsiveness, also demonstarting the amplification of their bioactivity.

From a synthetic standpoint, chitosan is especially attractive due to the presence of repeating NH₂ groups at its C2 position that allow various chemoselective modifications. The substituents’ effect was examined in terms of coupling yields, self-assembly, encapsulation capabilities, physical and mechanical features of the modified polymers. Interestingly, numerous analyses in this study have not followed a linear progression relating to substituent chain length, but a parabolic pattern with a specific extremum point. This unanticipated trend was further corroborated using a theoretical kinetic model. A basic understanding of the side chain effect is paramount for rational modifications of these biopolymers. The reported OPNs hold remarkable potential as biocompatible nanocarriers for the effective delivery of active agents in agriculture, medicine, and cosmetics.