Immunomechanical colloidal crystals orchestrate macrophage polarization for wound healing

<p>Bacterial infections at wound sites or following biomaterial implantation remain a major clinical challenge, often necessitating repeated surgical intervention. Here, we introduce BCCe6, a photodynamic and immunomodulatory colloidal self-assembled crystal (cSAC) fabricated from MnO₂-modified silica and chlorin e6 (Ce6)-functionalized polystyrene particles. The hierarchical structure, controlled Mn²⁺ ion release, and photodynamic properties of BCCe6 synergistically eradicate surrounding bacteria and biofilms. Beyond antibacterial effects, BCCe6 activates bone marrow–derived dendritic cells (BMDCs) and induces macrophage polarization toward the M1 phenotype. RNA sequencing revealed upregulation of inflammatory mediators (TLR and IL families) and activation of TNF-α and IL-17 signaling pathways. Moreover, BCCe6 exhibits unique mechanotransduction, activating the MAPK and PI3K/Akt pathways. qPCR and protein analyses confirmed downregulation of macrophage focal adhesion and cytoskeletal components upon contact with BCCe6. Mechanistically, macrophage polarization is regulated via dual immunomechanical axes: the integrin/PYK2 (biomechanical) and cGAS/STING (biochemical) signaling pathways. In a drug-resistant bacteria-infected wound model, BCCe6, combined with near-infrared (NIR) irradiation, rapidly triggered immune activation, eradicated bacterial contamination, and subsequently recruited M2 macrophages, thereby accelerating wound healing. This proof-of-concept study demonstrates that precisely tuned physicochemical cues of biomaterials can be harnessed to combat infection, modulate immunity, and promote tissue regeneration, providing new insights for the rational design of next-generation immunoregulatory biomaterials and advancing the field of materiobiology.</p>