Injectable hydrogel microspheres for sustained gene delivery of antisense oligonucleotides to restore the expression of dystrophin protein in duchenne muscular dystrophy

•We developed an injectable hydrogel delivery vehicle, namely PF microspheres, for the sustained delivery of antisense oligonucleotides (AONs), when applying an exon-skipping approach to treat Duchenne muscular dystrophy (DMD).•The in vitro release of the AONs was sustained for several weeks, concurrent to the degradation of the PF microspheres, and the released AONs were incorporated into murine myoblasts from mdx dystrophic mouse model.•The AON-laden PF microspheres were administered intramuscularly into the tibialis anterior muscle of mdx dystrophic mice to reveal a marked reduction in both inflammation and fibrosis scores after 30 days.•The microspheres proved effective by improving the AON pharmacokinetic properties, increasing their stability, and greatly decreasing the overall administered dosage.•This study is significant in that it provides the medical community with an injectable microsphere delivery system capable of controlled release of AONs for treating DMD.