Biofilm can protect bacteria from immune attacks and antibiotic inhibition, and bacterial biofilm hosted in implanted materials and medical devices is a serious threat for modern medical system. Herein, we report biofilm-responsive caged guanidine nanoparticles (CGNs) to deeply penetrate and accumulate in bacterial biofilm, and then efficient photothermal eradication of bacterial biofilm is achieved upon NIR laser irradiation via the proof-of-concept formulation of photothermal agents in CGNs. In physiological conditions and blood circulation, CGNs are negatively charged by masking the positive charge of guanidine via covalent modification with acid-cleavable moieties, exhibiting high biocompatibility and minimal hemolysis. Whereas upon blood circulation and passive accumulation at infected implant sites, CGNs are self-adaptive in acidic biofilm to release the protective caging group and expose native guanidine moieties, which can promote nanoparticle deep biofilm penetration and bacteria adhesion as well as membrane fusion. After that, remarkable photothermal effect with a high photothermal conversion efficiency of ∼40.9% can eradicate implant biofilm upon NIR laser irradiation. It can efficiently treat S. aureus biofilminfected implant catheters in vivo via only one single treatment in a mouse model, exhibiting ∼99.6% bacteria inhibition ratio. Apart from this proof-of-concept work, current guanidine-caged biofilm responsive polymeric nanoparticles are promising general vectors to treat biofilm and resistant pathogens in medicine and daily healthcare.
Highly pathogenic Gram-negative bacteria and their drug resistance
are a severe public health threat with high mortality. Gram-negative
bacteria are hard to kill due to the complex cell envelopes with low
permeability and extra defense mechanisms. It is challenging to treat
them with current strategies, mainly including antibiotics, peptides,
polymers, and some hybrid materials, which still face the issue of
drug resistance, limited antibacterial selectivity, and severe side
effects. Together with precise bacteria targeting, synergistic therapeutic
modalities, including physical membrane damage and photodynamic eradication,
are promising to combat Gram-negative bacteria. Herein, pathogen-specific
polymeric antimicrobials were formulated from amphiphilic block copolymers,
poly(butyl methacrylate)-b-poly(2-(dimethylamino)
ethyl methacrylate-co-eosin)-b-ubiquicidin,
PBMA-b-P(DMAEMA-co-EoS)-UBI, in
which pathogen-targeting peptide ubiquicidin (UBI) was tethered in
the hydrophilic chain terminal, and Eosin-Y was copolymerized in the
hydrophilic block. The micelles could selectively adhere to bacteria
instead of mammalian cells, inserting into the bacteria membrane to
induce physical membrane damage and out-diffusion of intracellular
milieu. Furthermore, significant in situ generation
of reactive oxygen species was observed upon light irradiation, achieving
further photodynamic eradication. Broad-spectrum bacterial inhibition
was demonstrated for the polymeric antimicrobials, especially highly
opportunistic Gram-negative bacteria, such as Pseudomona aeruginosa (P. aeruginosa) based on the synergy of physical
destruction and photodynamic therapy, without detectable resistance. In vivo P. aeruginosa-infected knife injury model and burn
model both proved good potency of bacteria eradication and promoted
wound healing, which was comparable with commercial antibiotics, yet
no risk of drug resistance. It is promising to hurdle the infection
and resistance suffered from highly opportunistic bacteria.
Herein, pathogen-targeting phototheranostic nanoparticles, Van-OA@PPy, are in situ developed for efficient elimination of MRSA infection, which is reflected by dual-modality magnetic resonance and photoacoustic imaging.
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