Macrophage-targeted dual-responsive hollow mesoporous silica nanosystem for photothermal and immunomodulatory elimination of intracellular MRSA

Cascade-targeting mannose-HMSNs enable dual macrophage and intracellular MRSA targeting. • pH/NIR dual-responsive nanoparticles promote lysosomal escape and drug release. • Photothermal IR780 and curcumin synergistically eradicate intracellular MRSA in vivo. • Curcumin-modulated M1/M2 polarization attenuates inflammation and enhances antibacterial efficacy. Intracellular bacterial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) pose serious threat to human health due to immune evasion and antibiotic resistance. Here, a new integrated drug delivery system (DDS) based on hollow mesoporous silica nanoparticles (HMSNs) with cascade-targeting, acidic/NIR dual responsive, photothermal antibacterial and immune modulation activities is reported. Mannose was grafted onto HMSNs through Schiff-base bond, resulting in Man-HMSNs. IR780 and curcumin (Cur) were coloaded into Man-HMSNs which resulted in the integrated drug delivery system, IR780/Cur@Man-HMSNs. The nanoparticles are specifically recognized and internalized by macrophages via mannose receptor recognition. Crucially, the acidic phagolysosome microenvironment triggers Schiff base cleavage to expose primary amine groups, achieving surface charge reversal from negative to positive that simultaneously promotes intracellular bacterial targeting through electrostatic adhesion and cargo release a cascade-targeting mechanism distinguishing this work from conventional HMSN platforms. Under NIR irradiation, photothermal and photodynamic effects directly eradicate intracellular MRSA while accelerating drug release. Cur enhances immune modulation by upregulating the M1/M2 polarization, which further promotes antibacterial capacity. In vitro, IR780/Cur@Man-HMSNs exhibits 92% MRSA biofilm eradication efficiency under acidic conditions. In vivo, it reduces the total bacterial burden to 2.45 log₁₀ CFU and achieves efficient intracellular MRSA elimination. IR780/Cur@Man-HMSNs show better intracellular bacteria elimination efficiency both in vitro and in vivo, compared with those of free IR780/Cur and individual IR780 or Cur loaded DDS. Therefore, the photothermal antibacterial and immune regulation integrated nanosystems with cascade targeting and acidic/NIR dual responsive properties provides a new method for treating intracellular bacterial infections. By mannose modification and co-loading of IR780 and curcumin, a multifunctional IR780/Cur@Man-HMSNs nanosystem was constructed for intracellular MRSA infection therapy. The nanosystem enables macrophage-mediated and intracellular bacteria cascade-targeting, undergoes surface charge reversal in acidic phagolysosomal microenvironments to promote bacterial interaction and lysosomal escape, and exhibits NIR-triggered drug release and photothermal antibacterial effects. Moreover, curcumin-mediated modulation of macrophage M1/M2 polarization alleviates inflammation and synergistically enhances antibacterial therapeutic efficacy. Download: Download high-res image (142KB) Download: Download full-size image