Cobweb‐Inspired Microenvironment‐Targeting Nanosystem with Sequential Multiple‐Stage Stimulus‐Response Capacity for Ischaemic Tissue Repair

Abstract

Myocardial ischaemia is pathologically complicated; various changes in intracellular and extracellular microenvironments make it essential to develop a smart drug system with multiple stimulus responses to adapt to the complex process. Inspired by the cobweb, this study designs a microreticular nanosystem that adheres to tissue and is sequentially responsive to multiple stimuli in the ischaemic microenvironment. The nanosystem is fabricated from hyaluronic acid (HA), ROS‐responsive B‐PDEA, and hypoxia‐sensitive VEGF‐expressing plasmids (EPODNA) through electrostatic interactions. After intramyocardial injection, the tissue‐adhesive property of the nanosystem will significantly decrease its acute loss from the injection site. Extracellularly, the microreticular nanosystem first responds to activated hyaluronidase (hyal), releasing HA for microenvironment regulation and B‐PDEA/DNA nanoparticles (NP) with high transfection efficiency for cardiac cells. Intracellularly, ROS sequentially induced B‐PDEA/DNA NP dissociation, consuming some ROS to attenuate oxidative stress and releasing DNA to promote its expression. Meanwhile, local hypoxia significantly activates VEGF expression in plasmids for myocardial revascularization and repair. The function of the microreticular nanosystem is systematically evaluated in vitro. In a rat model of myocardial infarction, treatment with the microreticular nanosystem significantly promotes functional and structural improvements. Collectively, the study provides a promising smart nanosystem to promote tissue repair after complex damage.

Amplified Targeted Drug Delivery Independent of Target Number through Alternative Administration of Two Matched Nanoparticles

“…In addition to tumor treatment, the applicability of amplified drug delivery was explored under other conditions, such as brain injury. Generally, the blood brain barrier (BBB) prevents drugs from entering brain tissues. − With brain injury, the integrity of the BBB is destroyed and drugs can enter the brain tissue. , However, the damaged BBB is largely restored in 1–2 days after injury and prevents the entry of drugs . Thus, the window of drug delivery for brain injuries is usually short.…”

“…The study provides a promising strategy for amplified targeted delivery of drugs that has potential applications in multiple disease models in the future. Despite this, this work still has a few limitations: (1) There is still no aptamer that is approved in clinical practice, and thus, it may take a long time for DNA-modified nanoparticles to be translated into clinical practice,though nanoparticles with DNA have been successively reported . (2) We did not determine the stability of matched NPs with time.…”

“…41,42 However, the damaged BBB is largely restored in 1−2 days after injury and prevents the entry of drugs. 43 Thus, the window of drug delivery for brain injuries is usually short. A promising resolution may be to deliver sufficient drugs with NPs in the window period of BBB damage while controlling the drug release in the expected time by using suitable NPs.…”

“…Despite this, this work still has a few limitations: (1) There is still no aptamer that is approved in clinical practice, and thus, it may take a long time for DNAmodified nanoparticles to be translated into clinical practice,though nanoparticles with DNA have been successively reported. 43 (2) We did not determine the stability of matched NPs with time. In the study, freshly prepared PLGA NPs were used, which would be rather inconvenient in practice.…”