Bee sting-shaped microneedles for accelerating Achilles tendinopathy healing via enhanced regulating macrophage polarization

Achilles tendinopathy (AT) is a common overuse injury to the Achilles tendon, and its progression is closely associated with an imbalance in M1/M2 macrophages and the inflammatory microenvironment. Traditional AT treatments are often limited by unwanted side effects, poor tissue penetration, and low therapeutic efficacy. Therefore, the targeted modulation of macrophage polarization could be a useful approach to relieve the inflammatory microenvironment of the Achilles tendon. In this study, we developed bee sting-shaped microneedles (DT-Exo-TMNs) to accelerate AT healing by enhancing the regulation of macrophage polarization. The DT-Exo-TMNs effectively reversed M1 macrophage polarization to M2 macrophage with a high efficiency of 43.4% by activating mitochondrial transcription factor A (TFAM). In addition, the photothermal agent, tannic acid /Fe 3+ , embedded in the DT-Exo-TMNs rapidly increased the temperature under near infrared (NIR) irradiation, significantly enhancing the antibacterial activity, promoting the release of therapeutic agents, and facilitating angiogenesis. In vivo experiments confirmed that DT-Exo-TMNs possess sufficient mechanical strength to insert the skin and deliver DT-Exo deep into tendon tissue in AT rat, thereby accelerating tendon repair through the synergistic alleviation of the inflammatory microenvironment and the regulation of immune homeostasis. In summary, these antibiotic-free, biocompatible, and multifunctional DT-Exo-TMNs hydrogel microneedles exhibit substantial potential for AT immunotherapy, providing a safe and effective therapeutic alternative for clinical applications.