Multifunctional pH-Responsive Microneedles Remodel Immunity and Activate HIF-1α for Alveolar Bone Regeneration.

Periodontitis, a highly prevalent chronic inflammatory disease, seriously threatens oral health by causing progressive alveolar bone resorption, vascular network destruction, and ultimately tooth loss. Current clinical strategies─including mechanical debridement, antibiotic therapy, and bone grafting─are often limited by inefficient local drug delivery, incomplete immunomodulation, and significant side effects. To address these challenges, we developed a multifunctional pH-responsive platform based on a dissolvable microneedle system incorporating deferoxamine (DFO)-loaded magnesium-aluminum layered double hydroxide (DFO@LDH). The LDH carrier possesses high drug-loading capacity and pH-dependent degradation characteristics, enabling controlled release of its components. Magnesium ions (Mg2+) released from the LDH framework modulate immune responses and promote osteogenesis, while the iron chelator DFO activates angiogenic pathways by stabilizing hypoxia-inducible factor-1α (HIF-1α). Leveraging the transdermal drug delivery properties of microneedles, DFO@LDH is delivered to local gingival tissues to achieve immunomodulation and tissue regeneration. This system is designed to overcome the main limitations of traditional microneedles, such as low drug loading, rapid release, and uncontrolled release. Furthermore, by remodeling the immune microenvironment, the system effectively counteracts inflammation-driven cellular senescence. This DFO@LDH microneedle system, which simultaneously targets immunomodulation, angiogenesis, osteogenesis, and senescence processes, provides a clinically translatable therapeutic strategy for periodontal regeneration, with potential applications in other inflammatory bone defects and chronic wound treatment areas.