Zoledronic acid-loaded dissolvable microneedle patch for targeted regulation of osteoblast/osteoclast homeostasis as a potential treatment for peri-implantitis.

Peri-implantitis is a major cause of dental implant failure, characterized by localized bone resorption driven by chronic inflammatory disruption of the balance between osteoblast and osteoclast activities, which ultimately leads to implant loosening and loss. Zoledronic acid (ZA) exerts potent inhibitory effects on osteoclasts and displays favorable bone-targeting properties; however, systemic administration of ZA carries a high risk of adverse reactions. To overcome this drawback, we fabricated hyaluronic acid-based dissolving microneedles loaded with zoledronic acid (ZA-DMNs) for local transmucosal delivery. This design aims to regulate the local osteoblast-osteoclast balance while eliminating systemic side effects to the greatest extent possible. The as-prepared ZA-DMNs possessed sufficient mechanical strength (withstanding a force of 0.15 N at half-height compression, exceeding the 0.1 N insertion threshold) and achieved a mucosal penetration depth of 140 μm, ensuring efficient transmucosal drug permeation. After insertion into mucosal tissue, the microneedle tips dissolved rapidly, releasing roughly 80% of the encapsulated ZA within 48 h. The liberated ZA binds tightly to bone surfaces with high affinity, locally suppressing osteoclast differentiation and bone resorptive activity. Furthermore, ZA-DMNs successfully rescued osteogenic function impaired by inflammatory microenvironments, and CCK-8 and live/dead staining assays confirmed their favorable biocompayibility. Taken together, these results preliminarily indicate that ZA-DMNs represent a promising local transmucosal delivery platform of ZA for the management of bone loss induced by peri-implantitis.