Pull‐and‐Push Nanotherapeutic Hydrogels: Scavenging Inflammatory Triggers While Driving Tissue Regeneration in Burn Wounds

ABSTRACT Burn wounds require dual therapeutic strategies: removing pro‐inflammatory damage‐associated molecular patterns (DAMPs) while delivering regenerative signals. Here, we report a nanounit‐assembled hydrogel embodying a “pull‐and‐push” approach for immune modulation and tissue repair. The hydrogel integrates cationic components (chitosan and PAMAM dendrimer) that scavenge (‘pull’) cell‐free DNA (cfDNA), a critical inflammatory DAMP, while simultaneously initiating regenerative programs through thermosensitive release (‘push’) of plerixafor (a CXCR4 antagonist) and bioactive ions (Ca 2+ and SiO 4 4− ) via NIPAAm polymer. The thermosensitive system responds to localized hyperthermia in burn‐wounded inflammation, while activating macrophage repolarization and angiogenesis. In vitro studies demonstrated efficient cfDNA scavenging, downregulation of pro‐inflammatory cytokines, and M2 polarization. In murine burn models, hydrogels accelerated re‐epithelialization, granulation tissue formation, and neovascularization. Spatial transcriptomic profiling reveals macrophage niches as functional hubs where pull‐and‐push mechanisms converge, driving stepwise reconfiguration from inflammatory suppression to repair‐permissive environments. By integrating cfDNA scavenging with thermally‐responsive dual delivery of therapeutics and bioactive ions, these multifunctional hydrogels provide a blueprint for next‐generation regenerative biomaterials.