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Precise Diabetic Wound Therapy: PLS Nanospheres Eliminate Senescent Cells via DPP4 Targeting and PARP1 Activation
Renliang Zhao1, Xiangyun Jin2, Ang Li1
1Department of Orthopedic Surgery and Shanghai Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Abstract:
Diabetic ulcers, a difficult problem faced by clinicians, are strongly associated with an increase in cellular senescence. Few empirical studies have focused on exploring a targeted strategy to cure diabetic wounds by eliminating senescent fibroblasts (SFs) and reducing side effects. In this study, poly-l-lysine/sodium alginate (PLS) is modified with talabostat (PT100) and encapsulates a PARP1 plasmid (PARP1@PLS-PT100) for delivery to target the dipeptidyl peptidase 4 (DPP4) receptor and eliminate SFs. PARP1@PLS-PT100 releases encapsulated plasmids, displaying high selectivity for SFs over normal fibroblasts by targeting the DPP4 receptor, decreasing senescence-associated secretory phenotypes (SASPs), and stimulating the secretion of anti-inflammatory factors. Furthermore, the increased apoptosis of SFs and the disappearance of cellular senescence alleviates SASPs, accelerates re-epithelialization and collagen deposition, and significantly induces macrophage M2 polarization, which mediates tissue repair and the inflammatory response. This innovative strategy has revealed the previously undefined role of PARP1@PLS-PT100 in promoting diabetic wound healing, suggesting its therapeutic potential in refractory wound repair.
Insights
This study introduces a novel therapy targeting senescent fibroblasts to heal diabetic ulcers. The new treatment effectively clears senescent cells, reduces inflammation, and promotes tissue repair for better wound healing.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Wound Healing Research
Background:
- Diabetic ulcers are a significant clinical challenge linked to cellular senescence.
- Current treatments lack targeted strategies to eliminate senescent fibroblasts (SFs) and minimize side effects.
Purpose of the Study:
- To develop and evaluate a targeted delivery system for eliminating SFs in diabetic wounds.
- To investigate the therapeutic potential of a novel poly-l-lysine/sodium alginate (PLS) nanoparticle system encapsulating a PARP1 plasmid (PARP1@PLS-PT100) modified with talabostat (PT100).
Main Methods:
- Modification of PLS with PT100 to create PARP1@PLS-PT100 for targeted delivery.
- Utilizing the dipeptidyl peptidase 4 (DPP4) receptor for selective targeting of SFs.
- Assessing the impact of PARP1@PLS-PT100 on senescence-associated secretory phenotypes (SASPs), fibroblast apoptosis, and macrophage polarization.
Main Results:
- PARP1@PLS-PT100 demonstrated high selectivity for SFs over normal fibroblasts via DPP4 receptor targeting.
- The treatment effectively decreased SASPs, stimulated anti-inflammatory factor secretion, and induced SF apoptosis.
- Observed acceleration in re-epithelialization, collagen deposition, and M2 macrophage polarization, crucial for tissue repair.
Conclusions:
- The PARP1@PLS-PT100 system offers a promising targeted strategy for diabetic wound healing by eliminating SFs.
- This innovative approach alleviates SASPs, promotes tissue regeneration, and suggests significant therapeutic potential for refractory wounds.
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