Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma
Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous and immunosuppressive malignancy that frequently exhibits poor responses to immunotherapy, primarily due to immune evasion mediated by myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Despite increasing interest...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
|
| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-025-03538-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849389364261421056 |
|---|---|
| author | Ziqi Guo Qiuling Huang Zhenzhen Cui Cheng Yang Liu Yang |
| author_facet | Ziqi Guo Qiuling Huang Zhenzhen Cui Cheng Yang Liu Yang |
| author_sort | Ziqi Guo |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous and immunosuppressive malignancy that frequently exhibits poor responses to immunotherapy, primarily due to immune evasion mediated by myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Despite increasing interest in MDSC-targeted strategies, effective approaches to selectively modulate MDSC function and enhance immunotherapeutic efficacy remain limited. Recent advances in nanotechnology have led to the development of nanodrug delivery systems, particularly for small interfering RNA (siRNA), offering advantages such as protection from degradation and improved delivery specificity. However, traditional liposomal carriers often suffer from low selectivity and widespread biodistribution, increasing the risk of off-target effects. In this study, we designed a pH-responsive lipid nanoparticle (Lip@si-YTHDF2) for the targeted delivery of siRNA against YTHDF2. This approach aimed to suppress MDSC function, inhibit CSC-mediated immune escape, and enhance immunotherapy in HCC. Bioinformatic analyses of GEO and TCGA-LIHC datasets revealed elevated YTHDF2 expression in HCC and its association with poor prognosis. Functional studies in a conditional YTHDF2-knockout mouse model demonstrated that YTHDF2 regulates MDSC activity and promotes tumor progression by stabilizing MYC mRNA through N6-methyladenosine (m6A) modification. Our findings demonstrated that Lip@si-YTHDF2 effectively downregulated MYC expression, diminished the immunosuppressive phenotype of MDSCs, restored T cell-mediated anti-tumor immunity, and significantly inhibited tumor growth in combination with PD-1 checkpoint blockade. This study not only elucidates a novel YTHDF2/m6A/MYC axis in immune evasion but also provides a clinically relevant siRNA delivery platform with promising therapeutic implications for improving HCC immunotherapy. Graphical Abstract |
| format | Article |
| id | doaj-art-2be6709c1df748f5b35d201a898db57d |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-2be6709c1df748f5b35d201a898db57d2025-08-20T03:41:59ZengBMCJournal of Nanobiotechnology1477-31552025-07-0123112710.1186/s12951-025-03538-0Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinomaZiqi Guo0Qiuling Huang1Zhenzhen Cui2Cheng Yang3Liu Yang4College of Life Sciences, Guangxi Normal UniversityCollege of Life Sciences, Guangxi Normal UniversityCollege of Life Sciences, Guangxi Normal UniversityCollege of Life Sciences, Guangxi Normal UniversityCollege of Life Sciences, Guangxi Normal UniversityAbstract Hepatocellular carcinoma (HCC) is a highly heterogeneous and immunosuppressive malignancy that frequently exhibits poor responses to immunotherapy, primarily due to immune evasion mediated by myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Despite increasing interest in MDSC-targeted strategies, effective approaches to selectively modulate MDSC function and enhance immunotherapeutic efficacy remain limited. Recent advances in nanotechnology have led to the development of nanodrug delivery systems, particularly for small interfering RNA (siRNA), offering advantages such as protection from degradation and improved delivery specificity. However, traditional liposomal carriers often suffer from low selectivity and widespread biodistribution, increasing the risk of off-target effects. In this study, we designed a pH-responsive lipid nanoparticle (Lip@si-YTHDF2) for the targeted delivery of siRNA against YTHDF2. This approach aimed to suppress MDSC function, inhibit CSC-mediated immune escape, and enhance immunotherapy in HCC. Bioinformatic analyses of GEO and TCGA-LIHC datasets revealed elevated YTHDF2 expression in HCC and its association with poor prognosis. Functional studies in a conditional YTHDF2-knockout mouse model demonstrated that YTHDF2 regulates MDSC activity and promotes tumor progression by stabilizing MYC mRNA through N6-methyladenosine (m6A) modification. Our findings demonstrated that Lip@si-YTHDF2 effectively downregulated MYC expression, diminished the immunosuppressive phenotype of MDSCs, restored T cell-mediated anti-tumor immunity, and significantly inhibited tumor growth in combination with PD-1 checkpoint blockade. This study not only elucidates a novel YTHDF2/m6A/MYC axis in immune evasion but also provides a clinically relevant siRNA delivery platform with promising therapeutic implications for improving HCC immunotherapy. Graphical Abstracthttps://doi.org/10.1186/s12951-025-03538-0pH-responsive nanoparticlesYTHDF2Myeloid-derived suppressor cellsm6A modificationsiRNA therapyHepatocellular carcinoma immunotherapy |
| spellingShingle | Ziqi Guo Qiuling Huang Zhenzhen Cui Cheng Yang Liu Yang Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma Journal of Nanobiotechnology pH-responsive nanoparticles YTHDF2 Myeloid-derived suppressor cells m6A modification siRNA therapy Hepatocellular carcinoma immunotherapy |
| title | Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma |
| title_full | Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma |
| title_fullStr | Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma |
| title_full_unstemmed | Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma |
| title_short | Targeting YTHDF2 with pH-responsive siRNA nanoparticles suppresses MYC m6A modification and restores antitumor immunity in hepatocellular carcinoma |
| title_sort | targeting ythdf2 with ph responsive sirna nanoparticles suppresses myc m6a modification and restores antitumor immunity in hepatocellular carcinoma |
| topic | pH-responsive nanoparticles YTHDF2 Myeloid-derived suppressor cells m6A modification siRNA therapy Hepatocellular carcinoma immunotherapy |
| url | https://doi.org/10.1186/s12951-025-03538-0 |
| work_keys_str_mv | AT ziqiguo targetingythdf2withphresponsivesirnananoparticlessuppressesmycm6amodificationandrestoresantitumorimmunityinhepatocellularcarcinoma AT qiulinghuang targetingythdf2withphresponsivesirnananoparticlessuppressesmycm6amodificationandrestoresantitumorimmunityinhepatocellularcarcinoma AT zhenzhencui targetingythdf2withphresponsivesirnananoparticlessuppressesmycm6amodificationandrestoresantitumorimmunityinhepatocellularcarcinoma AT chengyang targetingythdf2withphresponsivesirnananoparticlessuppressesmycm6amodificationandrestoresantitumorimmunityinhepatocellularcarcinoma AT liuyang targetingythdf2withphresponsivesirnananoparticlessuppressesmycm6amodificationandrestoresantitumorimmunityinhepatocellularcarcinoma |