Mito-battery: Micro-nanohydrogel microspheres for targeted regulation of cellular mitochondrial respiratory chain

The mitochondrial respiratory chain (MRC) plays an essential role in regulating cellular energy metabolism and oxidative stress. Repairing damaged MRC function can efficiently provide cells with energy to fight inflammation. Herein, with the inspiration by a rechargeable battery, microfluidics was used to prepare hyaluronic acid hydrogel microspheres as shells and con-covalently connected the inner core-SS-31 peptide and Wyrgrl peptide co-modified long-circulating liposomes loaded with resveratrol (REV) to the nanonetwork of microspheres to construct a "Mito-Battery" that could promote cell energy production and fight inflammation by targeted regulation of MRC functions. Modification of peptide could increase its cellular uptake and enhance the mitochondrial-targeting of "Mito-Battery." Meanwhile, REV loaded in the liposomes can activate SIRT3 protein and synergistically enhance the MRC electron transfer efficiency with SS-31. "Mito-Battery" effectively delayed the progression of the disease in a rat bone and joint model. Thus, "Mito-Battery" has great potential in the treatment of degenerative diseases related to MRC dysfunction.