A hesperidin-engineered metal-phenolic nanoplatform for biofilm-targeted and self-amplified photothermal/chemodynamic therapy of skin abscesses.

Abstract

Biofilm-associated skin abscesses remain challenging to manage because the extracellular polymeric matrix restricts drug access and bacteria rapidly activate protective stress programs. Here, we developed a hesperidin/Fe3+-assembled metal-phenolic nanoplatform functionalized with phenylboronic acid (HF@PBA) for biofilm-targeted photothermal/chemodynamic therapy. Hesperidin not only participates in nanoparticle assembly as a natural flavonoid ligand, but also contributes anti-biofilm bioactivity and efficient near-infrared photothermal responsiveness after coordination with Fe3+. PBA modification enhances adhesion to the extracellular polymeric matrix, improving retention and penetration within infectious lesions. Under 808 nm irradiation, HF@PBA enables mild photothermal therapy, while released hesperidin suppresses DnaK/HSP70-associated heat-stress tolerance. In the acidic and glutathione-rich biofilm microenvironment, the nanoparticles dissociate, releasing Fe3+, which is reduced to Fe2+ and subsequently drives hydroxyl radical generation. Meanwhile, hesperidin further interferes with quorum sensing and virulence-related responses. Consequently, HF@PBA effectively eliminated planktonic bacteria and mature biofilms in vitro, and transcriptomic/protein analyses revealed marked suppression of heat-shock and quorum-sensing pathways. In a murine MRSA abscess model, HF@PBA achieved 99.7% bacterial eradication, alleviated inflammation, and enhanced collagen regeneration and angiogenesis with negligible systemic toxicity. This work provides a simple biodegradable strategy for treating persistent biofilm-associated skin infections.