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Updated: Jun 29, 2025
Fabrication of Size-Controlled and Emulsion-Free Chitosan-Genipin Microgels for Tissue Engineering Applications
Published on: April 13, 2022
CPPs-modified chitosan as permeability-enhancing chemotherapeutic combined with gene therapy nanosystem by
Jie Cao1, Chenghong Zhu1, Ziqi Cao1
1Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu province, China.
Background:
Chemotherapy resistance of osteosarcoma (OS) is still the crux of poor clinical curative effect.E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin resistance in OS, which ultimately mediated DNA damage tolerance and led to a poor prognosis and chemotherapy response in patients.
Methods:
In this study, doxorubicin was loaded in the process of Fe2+ and siRad18 forming nanoparticles(FSD) through coordination, chitosan modified with cell penetrating peptide (H6R6) was synthesized and coated on the surface of the NPs(FSD-CHR). FSD-CHR was then dispersed in thermosensitive hydrogel(PPP) for peritumoral injection of osteosarcoma in situ. Subsequently, the physicochemical properties and molecular biological characteristics of the drug delivery system were characterized. Finally, an osteosarcoma model was established to study the anti-tumor effects of multifunctional nanoparticles and the immunotherapy effect combined with αPD-L1.
Results:
FSD-CHR has enhanced tumor tissue permeability, siRad18 can significantly reduce Dox-mediated DNA damage tolerance and enhance anti-tumor effects, and iron-based NPs show enhanced ROS upregulation. FSD-CHR@PPP showed significant inhibition of osteosarcoma growth in vivo and a reduced incidence of lung metastasis. In addition, siRad18 was unexpectedly found to enhance Dox-mediated immunogenic cell death (ICD).FSD-CHR@PPP combined with PD-L1 blocking significantly enhanced anti-tumor effects due to decreased PD-L1 enrichment.
Conclusion:
Hydrogel encapsulation of permeable nanoparticles provides an effective strategy for doxorubicin-resistant OS, showing that gene therapy blocking DNA damage tolerance can enhance treatment response to chemotherapy and appears to enhance the effect of ICD inducers to activate the immune system.
Insights
This study developed a novel nanoparticle system to overcome chemotherapy resistance in osteosarcoma. By blocking DNA damage tolerance with siRad18, the treatment enhanced chemotherapy effectiveness and activated anti-tumor immunity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Osteosarcoma (OS) chemotherapy resistance remains a significant clinical challenge, leading to poor patient outcomes.
- E3 ubiquitin-protein ligase Rad18 (Rad18) promotes doxorubicin resistance in OS by mediating DNA damage tolerance.
- Targeting Rad18 offers a potential strategy to enhance chemotherapy efficacy in osteosarcoma.
Purpose of the Study:
- To develop and characterize a multifunctional nanoparticle system for treating doxorubicin-resistant osteosarcoma.
- To evaluate the anti-tumor effects of the nanoparticle system, including its combination with immunotherapy.
- To investigate the role of siRad18 in overcoming chemotherapy resistance and enhancing immunogenic cell death (ICD).
Main Methods:
- Doxorubicin and siRad18 were loaded into iron-based nanoparticles (FSD), coated with cell-penetrating peptide-modified chitosan (FSD-CHR).
- FSD-CHR was encapsulated in a thermosensitive hydrogel (PPP) for peritumoral injection in an osteosarcoma model.
- The study assessed physicochemical properties, molecular characteristics, anti-tumor efficacy, and immunotherapy effects (combined with αPD-L1).
Main Results:
- The FSD-CHR@PPP system demonstrated enhanced tumor tissue permeability and significant inhibition of osteosarcoma growth in vivo.
- siRad18 effectively reduced doxorubicin-mediated DNA damage tolerance, enhancing anti-tumor effects and ROS upregulation.
- The combination therapy, particularly with PD-L1 blocking, significantly boosted anti-tumor responses by decreasing PD-L1 enrichment and enhancing ICD.
Conclusions:
- Hydrogel-encapsulated permeable nanoparticles offer a promising strategy for treating doxorubicin-resistant osteosarcoma.
- Gene therapy targeting DNA damage tolerance (siRad18) enhances chemotherapy response and activates the immune system.
- This approach shows potential for improving osteosarcoma treatment by combining chemotherapy, gene therapy, and immunotherapy.
