Infection-triggered surface remodeling for mucus penetration and host-pathogen reprogramming against MDR bacterial infections.

Mucosal bacterial infections, including pneumonia and keratitis, remain challenging to treat because the viscoelastic mucus barrier severely impedes drug transport. Although PEGylation is widely employed to facilitate mucus penetration, it often masks bacterial-binding motifs, creating a long-standing dilemma between efficient mucus traversal and effective pathogen targeting. Herein, we develop an infection-responsive nanoplatform (BPPC) that dynamically resolves this conflict through programmable surface remodeling. The BPPC consists of a phenylboronic acid-poly(ethylene glycol)-chlorin e6 (PBA-PEG-Ce6) conjugate armored with Bletilla striata polysaccharide (BSP) via acid-labile boronate ester bonds. The BSP/PEG dual-hydrophilic corona enables rapid diffusion across mucus barriers and efficient access to deep infection sites. Upon exposure to the mildly acidic infectious microenvironment, BSP is selectively shed, exposing latent PBA ligands for high-affinity bacterial anchoring. This infection-triggered transformation enhances local retention on multidrug-resistant Pseudomonas aeruginosa (MDR-PA) and enables potent resistance-independent bacterial eradication through Ce6-mediated photodynamic and sonodynamic therapy. Meanwhile, the released mannose-rich BSP acts as a bioactive immunomodulator that suppresses TLR4/NF-κB signaling and promotes macrophage polarization toward a pro-reparative M2 phenotype, thereby facilitating inflammation resolution. In murine models of MDR-PA-induced keratitis and pneumonia, BPPC achieved robust bacterial clearance, mitigated excessive inflammation, prevented fibrotic remodeling, and restored tissue homeostasis. By seamlessly integrating mucus-penetrating delivery, infection-activated pathogen sterilization, and host immune reprogramming, BPPC provides a versatile host-pathogen bidirectional strategy for managing refractory mucosal infections.