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 (α-CDs), as a carrier for localized delivery of poly(β-amino ester) (PBAE) and siRNA polyplexes. Polyplexes assembled within α-CDs showed higher sizes (150–300 nm) and positive charges (+20 to +30 mV) compared to those in HEPES buffer (<100 nm, −20 to +20 mV). SM hydrogels, prepared by mixing aqueous solutions of PEU and α-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 48 h 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.