Oxygen-enriching hollow MOF as nanobubbles to enhance treatment of hypertrophic scar via microneedle-mediated sonodynamic therapy.

Abstract

Hypertrophic scars (HS) are characterized by the over-proliferation of hypertrophic scar fibroblasts (HSFbs) and excessive deposition of a dense extracellular matrix (ECM), which collectively restrict the transdermal delivery and intralesional diffusion of therapeutic agents. Moreover, the hypoxic microenvironment, a prominent hallmark of HS, further exacerbates fibrosis and compromises therapeutic responses. Inspired by clinical ultrasonic microbubbles for cross-barrier transport, we have developed hollow porphyrinic metal-organic framework (H-PMOF) and, PFOB(O₂)@H-PMOF (HPPO) nanobubbles by encapsulating oxygen-enriched perfluorooctyl bromide (PFOB) into the hollow interior. To facilitate effective transdermal delivery, these HPPO nanobubbles were further integrated into a dissolving microneedle (MN) platform. The MOF architecture prevents porphyrin self-quenching through framework-mediated spatial isolation, while the hollow design significantly enhances sonodynamic therapy (SDT) efficacy compared with solid counterparts. Upon ultrasound (US) activation, the HPPO nanobubbles achieve dual "acoustic-physical and acoustic-chemical" responsiveness: the PFOB core induces acoustic cavitation to breach the dense fibrotic barrier and initiate oxygen release, while the H-PMOF shell mediates potent oxygen-augmented SDT. In vitro and in vivo experiments confirmed that the HPPO nanobubbles-integrated microneedle patch (HPPO MN) achieved a synergistic "triple-action" effect of "enhanced penetration, hypoxia alleviation, and high-efficiency SDT", providing a new approach for the precision treatment of deep pathological scars.