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Indolicidin-Decorated Photosensitizer for Enhanced Antibacterials and Accelerated Diabetic Wound Healing
Xiang Chen1, Zhanming Lin1, Yongjun Mo2
1Department of Bone and Joint Surgery (Guangxi Diabetic Foot Salvage Engineering Research Center/Research Centre for Regenerative Medicine), the First Affiliated Hospital of Guangxi Medical University, Nanning, P. R. China.
Abstract:
Diabetic wounds are difficult to heal due to infections caused by multidrug-resistant bacteria. Although photodynamic therapy (PDT) and antimicrobial peptides (AMPs) have emerged as promising alternatives, each faces inherent limitations: PDT-generated reactive oxygen species (ROS) have an extremely short lifespan (10-320 ns) and limited diffusion (10-55 nm), while AMPs are structurally unstable, potentially cytotoxic at high doses, and even induce bacterial resistance. To overcome these drawbacks, we developed a synergistic nanoplatform by integrating the AMP Indolicidin with the photosensitizer PTBT, further encapsulated within a thermosensitive F127 hydrogel (PTBT/I@F127). The system formed uniform, highly photosensitive nanoparticles in which Indolicidin, located on the outer surface, first disrupted bacterial membranes, facilitating the contact of PTBT with bacteria. Subsequently, abundant ROS were generated for rapidly killing bacteria under an 808-nm laser irradiation, which effectively compensated for the limited diffusion of ROS and reinforced the antibacterial effect of Indolicidin before its degradation. In vitro, PTBT/I@F127 effectively killed methicillin-resistant Staphylococcus aureus (MRSA) and E. coli with a remarkable synergy. In diabetic mice and pig models, wound healing rates reached 98% and 83%, respectively, with remarkable angiogenesis and collagen deposition, after receiving PTBT/I@F127. Transcriptomic analysis revealed that Wnt/β-catenin signaling pathways were involved in promoting tissue regeneration, while inflammation-associated signaling pathways, such as NF-κB and IL-17, were concurrently regulated, thereby alleviating inflammation and reshaping the immune microenvironment in infected wounds. Collectively, this PTBT/Indolicidin-based thermosensitive hydrogel effectively eliminated resistant bacteria, mitigated inflammation, stimulated angiogenesis, and accelerated healing of infected diabetic wounds, offering a safe, controllable, and translationally promising therapeutic strategy.
Insights
A new nanoplatform combines an antimicrobial peptide and photodynamic therapy to effectively treat infected diabetic wounds. This innovative hydrogel therapy accelerates healing by killing resistant bacteria and promoting tissue regeneration.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Wound Healing Research
Background:
- Diabetic wounds present significant healing challenges due to multidrug-resistant bacterial infections.
- Existing treatments like photodynamic therapy (PDT) and antimicrobial peptides (AMPs) have limitations in ROS diffusion, stability, and potential resistance.
- Developing advanced therapeutic strategies is crucial for overcoming these obstacles in diabetic wound management.
Purpose of the Study:
- To develop a synergistic nanoplatform integrating an AMP (Indolicidin) and a photosensitizer (PTBT) within a thermosensitive hydrogel (F127) for enhanced diabetic wound treatment.
- To investigate the combined therapeutic effects of the nanoplatform against multidrug-resistant bacteria and its efficacy in promoting wound healing.
- To elucidate the underlying molecular mechanisms, including signaling pathways involved in tissue regeneration and immune modulation.
Main Methods:
- Fabrication of a thermosensitive hydrogel encapsulating PTBT and Indolicidin (PTBT/I@F127) nanoparticles.
- In vitro assessment of antibacterial efficacy against MRSA and E. coli, evaluating synergistic effects.
- In vivo studies in diabetic mice and pig models to evaluate wound healing rates, angiogenesis, and collagen deposition.
- Transcriptomic analysis to identify key signaling pathways (e.g., Wnt/β-catenin, NF-κB) involved in the therapeutic response.
Main Results:
- The PTBT/I@F127 nanoplatform demonstrated potent synergistic antibacterial activity, effectively killing MRSA and E. coli.
- In vivo studies showed accelerated wound healing, with rates of 98% in mice and 83% in pigs, accompanied by significant angiogenesis and collagen deposition.
- Transcriptomic analysis revealed modulation of Wnt/β-catenin for tissue regeneration and regulation of NF-κB and IL-17 pathways, indicating reduced inflammation and reshaped immune microenvironment.
Conclusions:
- The developed PTBT/Indolicidin-based thermosensitive hydrogel is a highly effective therapeutic strategy for infected diabetic wounds.
- This nanoplatform overcomes limitations of individual therapies by synergistic bacterial elimination, inflammation mitigation, and promotion of wound regeneration.
- The findings suggest a safe, controllable, and translationally promising approach for treating complex diabetic wound infections.
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