Design of an injectable and bioerodible supramolecular hydrogel as a local nucleic acid delivery system

Although RNA therapeutics hold great promise for treating different diseases, their administration across physiological barriers remains challenging. This study explores a supramolecular (SM), bioerodible, and injectable hydrogel, composed of an ad hoc synthesized Poloxamer 407-based poly(ether urethane) (PEU) and α-cyclodextrins (alfa-CDs), as a carrier for localized delivery of poly(beta-aminoester) (PBAE) and siRNA polyplexes. Polyplexes assembled within alfa-CDs showed higher sizes (150−300nm) and positive charges (+20 to +30mV) compared to those in HEPES buffer (<100nm, −20 to +20mV). SM hydrogels, prepared by mixing aqueous solutions of PEU and alfa-CDs at final concentrations of 0.9−1.4 and 10%w/v, respectively, preserved thixotropic and self-healing characteristics after polyplex embedding. Intact polyplexes were released from the hydrogel over 48h and showed efficient gene knockdown in phagocytic cells. These findings underscore the potential of SM hydrogels as gene delivery vehicles, premised upon their injectability and favorable release profiles.