Nanoscale coordination polymer-coated microneedle patches against bacterial biofilm infection via hypoxia-enhanced copper ion interference therapy

Ion interference therapy (IIT) represents an intervention strategy aimed at modulating the intracellular distribution of functional ions to mitigate bacterial biofilm infections (BBI). However, bacteria tend to activate protective pathways to alleviate the damage induced by ion interference under stress conditions, substantially diminishing the long-term therapeutic efficacy of IIT. Herein, we proposed an antibiofilm strategy of the photodynamic therapy (PDT)-mediated hypoxia-enhanced copper ion interference therapy (PHCIIT). The double-layered microneedles (CuIA@SCC MN) were synthesized by integrating the novel copper-coordinated polymeric nanorods (CuIA NRs) with sodium copper chlorophyllin (SCC) on the surface of hydrogel microneedles. Compared to conventional copper ion therapy, treatment with CuIA@SCC MN resulted in the PDT-mediated hypoxic microenvironment, enhancing the copper toxicity by inhibiting the protective mechanisms of bacteria, including down-regulation of multicopper oxidase activity and the enhanced accumulation of monovalent copper ions. Furthermore, the sustained release of therapeutic copper ions from CuIA NRs within the micro-acidic biofilm would further aggravate copper overload. The efficacy of the PHCIIT strategy was validated using diabetic wounds infected with E. coli biofilm. Following PHCIIT intervention, macrophages in the infected tissues exhibited polarization towards the M2-like phenotype, which could expedite wound healing. It is believed that the PHCIIT-based strategy is highly significant in advancing conventional IIT.