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Targeted S100A8 PP-Cas9@PLGA-apt microparticles reduced cartilage degradation and subchondral bone isomerism in
Zhong Chen1, Miaomiao Zhou2, Jialong Luo1
1Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, PR China.
Abstract:
Synovial inflammation caused by osteoarthritis (OA) results in the release of numerous pro-inflammatory factors that promote cartilage degradation and pathological changes of subchondral bone. Nowadays, S100A8 has been recognized as a critical factor in the progression of inflammatory diseases, but its role in OA still needs to be confirmed. At the same time, the gene editing technology has emerged as a novel therapeutic approach for OA, such as clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) technology, but application in inflammatory gene therapy still requires advanced delivery systems to ensure cell-specific targeting and biosafety. In this study, S100A8 was confirmed as a key mediator perpetuating JAK/STAT3 pathway activation in OA progression by integrated RNA bioinformatics and synovial proteomic analyses. Based on it, we developed a polyamidoamine (PAMAM)-poly (lactic-co-glycolic acid) (PLGA) (PP) nanocore electrostatically complexed with Cas9-S100A8, encapsulated within an aptamer (apt)-grafted PLGA shell structure. This multifunctional nanocarrier could reduce dendrimer toxicity to cells and protein degradation, and enhance cellular targeting and endocytic capacity. PP-Cas9-S100A8@PLGA-apt exhibited 64.4 % S100A8 knockout efficiency (p < 0.001) and sustained mRNA release (71.5 % retention at 48 h), high cell viability (>80 %), and synovium-specific uptake (98.8 % at 0.8 μg/mL), inhibiting the JAK/STAT3 pathway. In OA-induced mice, this inhibition reduced pro-inflammatory responses, cartilage degradation, and attenuated osteophyte volume. Our findings first established PP-Cas9-S100A8@PLGA-apt as an efficient and safe Cas9 delivery tool, advancing studies of JAK/STAT3 pathway inhibition and the clinical translation of gene therapy for OA.
Insights
This study identifies S100A8 as a key driver of osteoarthritis (OA) inflammation and develops a novel aptamer-grafted nanocarrier for CRISPR/Cas9 gene therapy delivery to effectively reduce OA progression.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Immunology
Background:
- Osteoarthritis (OA) involves synovial inflammation, cartilage degradation, and subchondral bone changes, driven by pro-inflammatory factors.
- S100A8 is implicated in inflammatory diseases, but its specific role in OA pathogenesis requires further elucidation.
- Gene editing technologies like CRISPR/Cas9 offer therapeutic potential for OA, necessitating advanced delivery systems for targeted and safe application.
Purpose of the Study:
- To confirm S100A8 as a critical mediator in OA progression by activating the JAK/STAT3 pathway.
- To develop a multifunctional nanocarrier for efficient and safe delivery of CRISPR/Cas9 targeting S100A8 for OA gene therapy.
- To evaluate the therapeutic efficacy of the developed nanocarrier in preclinical OA models.
Main Methods:
- Integrated RNA bioinformatics and synovial proteomic analyses to identify key mediators in OA.
- Development of a polyamidoamine (PAMAM)-poly (lactic-co-glycolic acid) (PLGA) (PP) nanocore complexed with Cas9-S100A8 and encapsulated in an aptamer-grafted PLGA shell (PP-Cas9-S100A8@PLGA-apt).
- In vitro assessment of knockout efficiency, cell viability, cellular targeting, and JAK/STAT3 pathway inhibition. In vivo evaluation in OA-induced mice.
Main Results:
- S100A8 was confirmed as a key mediator perpetuating JAK/STAT3 pathway activation in OA.
- The developed nanocarrier (PP-Cas9-S100A8@PLGA-apt) achieved 64.4% S100A8 knockout efficiency with high cell viability (>80%) and synovium-specific uptake (98.8%).
- In vivo, the treatment reduced pro-inflammatory responses, cartilage degradation, and osteophyte volume in OA-induced mice by inhibiting the JAK/STAT3 pathway.
Conclusions:
- The study establishes PP-Cas9-S100A8@PLGA-apt as an effective and safe delivery tool for CRISPR/Cas9 gene therapy in OA.
- This nanocarrier demonstrates significant potential for inhibiting the JAK/STAT3 pathway and mitigating OA pathology.
- The findings advance the development of gene therapy strategies for OA clinical translation.
