Accurate Spatio-Temporal Delivery of Nitric Oxide Facilitates the Programmable Repair of Avascular Dense Connective Tissues Injury.

Avascular dense connective tissues (e.g., the annulus fibrosus (AF) rupture, the meniscus tear, and tendons and ligaments injury) repair remains a challenge due to the "biological barrier" that hinders traditional drug permeation and limits self-healing of the injured tissue. Here, accurate delivery of nitric oxide (NO) to penetrate the "AF biological barrier" is achieved thereby enabling programmable AF repair. NO-loaded BioMOFs are synthesized and mixed in a modified polyvinyl alcohol and PCL-composited electrospun fiber membrane with excellent reactive oxygen species-responsive capability (LN@PM). The results show that LN@PM could respond to the high oxidative stress environment at the injured tissue and realize continuous and substantial NO release. Based on low molecular weight and lipophilicity, NO could penetrate through the "biological barrier" for accurate AF drug delivery. Moreover, the dynamic characteristics of the LN@PM reaction can be matched with the pathological microenvironment to initiate programmable tissue repair including sequential remodeling microenvironment, reprogramming the immune environment, and finally promoting tissue regeneration. This tailored programmable treatment strategy that matches the pathological repair process significantly repairs AF, ultimately alleviating intervertebral disc degeneration. This study highlights a promising approach for avascular dense connective tissue treatment through intelligent NO release, effectively overcoming "AF biological barriers" and programmable treatment.