Controlled Release of Exosomes Using Atom Transfer Radical Polymerization-Based Hydrogels

Abstract

Exosomes are 30−200 nm sized extracellular vesicles that are increasingly recognized as potential drug delivery vehicles. However, exogenous exosomes are rapidly cleared from the blood upon intravenous delivery, which limits their therapeutic potential. Here, we report bioactive exosome-tethered poly-(ethylene oxide)-based hydrogels for the localized delivery of therapeutic exosomes. Using cholesterol-modified DNA tethers, the lipid membrane of exosomes was functionalized with initiators to graft polymers in the presence of additional initiators and crosslinker using photoinduced atom transfer radical polymerization (ATRP). This strategy of tethering exosomes within the hydrogel network allowed their controlled release over a period of 1 month, which was much longer than physically entrapped exosomes. Exosome release profile was tuned by varying the crosslinking density of the polymer network and the use of photocleavable tethers allowed stimuli-responsive release of exosomes. The therapeutic potential of the hydrogels was assessed by evaluating the osteogenic potential of bone morphogenetic protein 2-loaded exosomes on C2C12 and MC3T3-E1 cells. Thus, ATRP-based exosome-tethered hydrogels represent a tunable platform with improved efficacy and an extended-release profile.

Open-air green-light-driven ATRP enabled by dual photoredox/copper catalysis

“…Nucleic acid-polymer conjugates represent another important class of biohybrids used as multifunctional biomaterials in nanoscience and biomedicine. 91,104,[108][109][110] Therefore, we decided to use the EY/Cu technique to gra polymers from DNA. A 23mer DNA-based macroinitiator (DNA-iBBr) with a-bromoisobutyrate group at the 5 ′ -end was prepared in a DNA synthesizer 111 and then extended with OEOMA 500 , and molar ratios of [OEOMA 500 ]/[DNA-iBBr]/[EYH 2 ]/[CuBr 2 ]/[TPMA] ¼ 600/1/0.03/ 0.6/1.8 at a low reaction volume of 250 mL (Fig.…”

Exosome inspired photo-triggered gelation hydrogel composite on modulating immune pathogenesis for treating rheumatoid arthritis

“…As encapsulating exosomes within the hydrogel network can effectively prolong exosome release and consumption for enhancing therapeutic efficacy [ 39 , 40 ], OE-MSC-Exos were loaded into silk fibroin based photo-crosslinkable hydrogel (SFMA). Photographs in Fig.…”

Extracellular vesicle-loaded hydrogels for tissue repair and regeneration

“…Yerneni et al. [ 124 ] designed an ATRP-based hydrogel (using cholesterol-modified DNA tethers, the lipid membrane of exosomes was functionalized with initiators to graft polymers in the presence of additional initiators and crosslinker using photoinduced ATRP) for the controlled release of EVs and found that the release time of EVs was significantly prolonged up to one month. This hydrogel delivery system showed great potential.…”

“… [ 23 ] Atom transfer radical polymerization (ATRP) nonactivated macrophages J774A.1 30–150 ​nm up to one month The monomer-to-crosslinker ratio (molar ratio) and the crosslinking density of the polymer networks both affect the release of EVs. [ 124 ] Ureido-pyrimidinone (UPy) supramolecular (PEG coupled to two UPy units) CPCs 100 ​nm up to 2.5 weeks The molecular weight of the PEG block within it may result in different kinetics of release. With a PEG block of 10 ​kg ​mol −1 (UPy10 ​k) showed a steadier release than UPy20 ​k.…”