Biomimetic polysaccharide-cloaked lipidic nanovesicles/microassemblies for improving the enzymatic activity and prolonging the action time for hyperuricemia treatment

Abstract

The improvement and maintenance of enzymatic activities represent major challenges. However, to address these we developed novel biomimetic polysaccharide hyaluronan (Hn)-cloaked lipidic nanovesicles (BHLN) and microassemblies (BHLNM) as enzyme carriers that function by entrapping enzymes in the core or by tethering them to the inner/outer surfaces via covalent interactions. The effectiveness of these enzyme carriers was demonstrated through an evaluation of the enzymatic activity and anti-hyperuricemia bioactivity of urate oxidase (also called uricase, Uase). We showed that Uase was effectively loaded within the BHLN/BHLNM (UHLN/UHLNM) and maintained good enzymatic bioactivity through a range of effects, including isolation from the external environment due to the vesicle-carrying (shielding effect), avoidance of recognition by the reticuloendothelial system due to Hn-cloaking (long-term effect), production of beneficial conformational changes (allosteric effect) due to a favorable internal microenvironment of construction and vesicle loading, and stabilization due to the reversible conjugation of Uase or vesicle and serum albumin (deposit effect). UHLN/UHLNM had significantly increased bioavailability (∼533% and ∼331% compared to Uase) and demonstrated greatly improved efficacy, whereby the time required for UHLN/UHLNM to lower the plasma uric acid concentration to a normal level was much shorter than that for free Uase. The interactions of the therapeutic enzyme (Uase), biomimetic membrane components (Hn and phospholipid), and serum albumin were investigated with a fluorescent probe and computational simulations to help understand the superior properties of UHLN/UHLNM.