Hyaluronidase‐Loaded Hyaluronated Liposomes for Time‐Dependent Structural Destabilization and Programmed Drug Release

This study presents the design of hyaluronated liposomes (HDOC@Lipo) engineered to undergo time‐dependent disassembly in response to hyaluronidase (HAase). Hyaluronic acid–deoxycholic acid (HA–DOCA, HDOC x ) conjugates with varying degrees of DOCA substitution ( x = 0.80, 0.45, 0.20, and 0.10) were incorporated into hydrogenated soy phosphatidylcholine (HSPC)‐based liposomal membranes. Upon HAase exposure, the liposomes exhibited distinct degradation and release kinetics governed by DOCA content. After 4 h of incubation, both HDOC 0.80 @Lipo and HDOC 0.45 @Lipo retained most of the encapsulated doxorubicin (DOX), releasing only 24–27 wt.%, whereas HDOC 0.20 @Lipo released 38 wt.%. The higher HAase susceptibility of HDOC 0.20 @Lipo resulted in 60 wt.% DOX release after 12 h, with cumulative release reaching 57%, 61%, and 74% at 48 h for HDOC 0.80 @Lipo, HDOC 0.45 @Lipo, and HDOC 0.20 @Lipo, respectively. Collectively, these results reveal that lower DOCA content facilitates enzymatic accessibility and accelerates HA degradation, thereby enabling controlled and tunable drug release. HDOC@Lipo thus represents a promising time‐programmed delivery platform for precision‐controlled cancer therapeutics.