A "controlled CO release" and "pro-angiogenic gene" dually engineered stimulus-responsive nanoplatform for collaborative ischemia therapy

Ischemic injury is mostly caused by insufficient blood supply, excessive inflammation and increased oxidative stress. Pro-angiogenic gene delivery can foster vascular remodeling and increase blood perfusion, but the adverse ischemia microenvironment leads to inadequate therapy effect and high recurrence rate. A novel combination strategy should be developed for the effective therapy of ischemic injury via remediating microenvironment and accelerating revascularization simultaneously. Carbon monoxide (CO) exhibits multiple bio-functions, especially anti-inflammation and anti-oxidant effects, suggesting that it might be an attractive candidate for ischemia therapy. Herein, for the first time, "controlled CO release" was introduced to treat limb ischemia. We developed the controlled CO delivery nanoplatform (PR@CORM) via encapsulating CO-releasing molecule-401 by the stimulus-responsive and ECs-adhesive peptide functionalized nanocarrier. In response to oxidants, PR@CORM can intelligently release therapeutic CO gas to remediate the microenvironment, but the pro-angiogenic effect is still disappointing. We thereby combined "CO therapy" and "pro-angiogenic gene therapy" to achieve the cooperative effects for ischemia therapy. This strategy exhibits superiority in the treatment of ischemic injury through extensively normalizing the microenvironment and accelerating revascularization. The "controlled CO release" serves as a scavenger of inflammation and reactive oxygen species, and pro-angiogenic gene holds potential for ischemia therapy.