A Temporally Programmed Microneedles Platform for Long-Acting Regulation and Rapid Sensing of Systemic Copper...

Developing a minimally invasive platform capable of simultaneously enabling long-acting copper metabolism regulation and rapid copper sensing remains a critical unmet challenge in addressing systemic copper dyshomeostasis. Here, we report a temporally programmed dual-module microneedles platform integrating bio-inspired nanosponges (BQMNPs) as an intradermal microreservoir system with combined diagnostic and therapeutic functions. BQMNPs are constructed by encapsulating quercetin and morin within cyclodextrin nanosponges, which are subsequently incorporated into two distinct microneedle modules: polylactic-co-glycolic acid (PLGA)-based therapeutic microneedles (T-MNs) and hyaluronic acid (HA)-based diagnostic microneedles (D-MNs). In vitro, BQMNPs exhibit multifunctional performance, enabling Cu²⁺ imaging while simultaneously improving cell viability and attenuating inflammatory cytokine expression in Cu²⁺-induced injury and oxidative stress cell models. In a high-copper/high-glucose mouse model, the T-MNs module allows sustained BQMNP release for over 10 days, achieving long-acting restoration of copper homeostasis, mitigation of Cu²⁺-induced hyperglycemia, and systemic detoxification. Remarkably, sustained copper homeostasis regulation markedly suppresses brain inflammation, thereby alleviating Cu²⁺-mediated tissue injury. Concomitantly, a fast-dissolving D-MNs module provides rapid intradermal Cu²⁺ sensing in vivo, synchronizing Cu²⁺ sensing with prolonged systemic intervention. This temporally programmed theranostic microneedle architecture offers a versatile strategy for precision regulation of metal-ion homeostasis and may inspire new therapeutic approaches for metabolic and neurodegenerative diseases.