Inducing In Situ M ₂ Macrophage Polarization for Tendinopathy Therapy through Microneedle Patch-Mediated Instant/Sustained Delivery of Rosmarinic Acid

Tendinopathy markedly impairs patients' quality of life, yet effective therapies remain limited. Conventional therapeutic strategies have largely overlooked the pivotal role of macrophages (M_φ) and M_φ-mediated immunoregulation in this condition. To address this, we designed a microneedle patch (MP) for the in situ delivery of rosmarinic acid (RosA), aiming to modulate local M_φ phenotype. We evaluated the therapeutic efficacy of this RosA-MP against tendinopathy and investigated the underlying mechanism. Briefly, the RosA-MP was fabricated by incorporating RosA into a microneedle array composed of poly(hydroxyethyl methacrylate-co-3-acrylamidophenyl boronic acid-co-(3-methacrylamidopropyl)trimethylammonium chloride) [poly(HEMA-co-3APBA-co-MAPTAC)], which was covalently linked to a flexible filter paper matrix. Formation of phenylboronic acid ester bonds between the 3APBA moieties and RosA endowed the RosA-MP with enhanced stiffness and skin penetration capability, facilitating sustained RosA release. Furthermore, the MAPTAC moieties provided instant hydrophilic swelling upon skin insertion, accelerating RosA delivery via increased internal osmotic pressure. In vitro and in vivo assays demonstrated that the RosA-MP simultaneously induced in situ M₂ M_φ polarization and scavenged reactive oxygen species. Mechanistic investigation revealed that suppression of the NLRP3 inflammasome contributed to the rationale behind M_φ polarization. Using a collagenase type I-induced rat tendinopathy model, we assessed the therapeutic effects of the RosA-MP. Results confirmed that the RosA-MP effectively treated tendinopathy and exhibited significant advantages over injection therapy.