Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathways
Recent studies have demonstrated that the human antimicrobial peptide LL37 plays a critical role in immune regulation under both normal physiological conditions and during disease progression, as evidenced by its elevated levels observed in various chronic inflammatory diseases. A deeper understandi...
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Elsevier
2025-08-01
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| author | Yushuang Wei Wenwen Li Rong Xu Cheng Xu Xiangyang Li Ning Li Fengdan Xu Kai Yang Bing Yuan |
| author_facet | Yushuang Wei Wenwen Li Rong Xu Cheng Xu Xiangyang Li Ning Li Fengdan Xu Kai Yang Bing Yuan |
| author_sort | Yushuang Wei |
| collection | DOAJ |
| description | Recent studies have demonstrated that the human antimicrobial peptide LL37 plays a critical role in immune regulation under both normal physiological conditions and during disease progression, as evidenced by its elevated levels observed in various chronic inflammatory diseases. A deeper understanding of its mechanism is essential for elucidating associated physiological and pathological processes, as well as for designing effective immune adjuvants and clinical therapeutics. In this study, we report that LL37 facilitates the assembly of unmethylated CpG dinucleotides (CpG ODNs), a clinically relevant immune adjuvant, into non-crystalline nanoparticles (NPs) with controlled size and zeta potential in a charge ratio-dependent manner. These assembled NPs enter cells via receptor-mediated macropinocytosis, coupled with LL37-mediated membrane penetration, thereby significantly enhancing cellular uptake of CpG compared to CpG alone, which enters cells through clathrin-mediated endocytosis. Consequently, the enhanced internalization of LL37-CpG NPs markedly boosts TNF-α production (>3.5-fold) in macrophages through interactions with lysosomal TLR9. This immunostimulatory mechanism offers an alternative perspective on how LL37 modulates nucleic acid assembly and activates immune cells, providing guidance for the application of peptide-CpG ODN complexes in vaccine adjuvants and immune modulation for disease treatment. |
| format | Article |
| id | doaj-art-ad9d533ada3c4123b33badf06bc71a48 |
| institution | OA Journals |
| issn | 2590-0064 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
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| series | Materials Today Bio |
| spelling | doaj-art-ad9d533ada3c4123b33badf06bc71a482025-08-20T02:20:51ZengElsevierMaterials Today Bio2590-00642025-08-013310201110.1016/j.mtbio.2025.102011Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathwaysYushuang Wei0Wenwen Li1Rong Xu2Cheng Xu3Xiangyang Li4Ning Li5Fengdan Xu6Kai Yang7Bing Yuan8Songshan Lake Materials Laboratory, Dongguan, 523808, Guangdong, China; Corresponding author.Songshan Lake Materials Laboratory, Dongguan, 523808, Guangdong, ChinaNational Laboratory of Solid State Microstructures and Department of Physics, Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, Jiangsu, China; Songshan Lake Materials Laboratory, Dongguan, 523808, Guangdong, ChinaSongshan Lake Materials Laboratory, Dongguan, 523808, Guangdong, ChinaSongshan Lake Materials Laboratory, Dongguan, 523808, Guangdong, ChinaDepartment of Neonatology, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, 523325, Guangdong, ChinaDepartment of Neonatology, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, 523325, Guangdong, ChinaCenter for Soft Condensed Matter Physics and Interdisciplinary Research & School of Physical Science and Technology, Soochow University, Suzhou, 215006, Jiangsu, China; Corresponding author.Songshan Lake Materials Laboratory, Dongguan, 523808, Guangdong, China; Corresponding author.Recent studies have demonstrated that the human antimicrobial peptide LL37 plays a critical role in immune regulation under both normal physiological conditions and during disease progression, as evidenced by its elevated levels observed in various chronic inflammatory diseases. A deeper understanding of its mechanism is essential for elucidating associated physiological and pathological processes, as well as for designing effective immune adjuvants and clinical therapeutics. In this study, we report that LL37 facilitates the assembly of unmethylated CpG dinucleotides (CpG ODNs), a clinically relevant immune adjuvant, into non-crystalline nanoparticles (NPs) with controlled size and zeta potential in a charge ratio-dependent manner. These assembled NPs enter cells via receptor-mediated macropinocytosis, coupled with LL37-mediated membrane penetration, thereby significantly enhancing cellular uptake of CpG compared to CpG alone, which enters cells through clathrin-mediated endocytosis. Consequently, the enhanced internalization of LL37-CpG NPs markedly boosts TNF-α production (>3.5-fold) in macrophages through interactions with lysosomal TLR9. This immunostimulatory mechanism offers an alternative perspective on how LL37 modulates nucleic acid assembly and activates immune cells, providing guidance for the application of peptide-CpG ODN complexes in vaccine adjuvants and immune modulation for disease treatment.http://www.sciencedirect.com/science/article/pii/S2590006425005812Single-stranded nucleic acidsSelf-assembled nanoparticleLL37Immune regulationCell internalization |
| spellingShingle | Yushuang Wei Wenwen Li Rong Xu Cheng Xu Xiangyang Li Ning Li Fengdan Xu Kai Yang Bing Yuan Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathways Materials Today Bio Single-stranded nucleic acids Self-assembled nanoparticle LL37 Immune regulation Cell internalization |
| title | Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathways |
| title_full | Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathways |
| title_fullStr | Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathways |
| title_full_unstemmed | Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathways |
| title_short | Multivalent Co-assembly of LL37-CpG nanoparticles: Enhanced immune response through activating multiple cell internalization pathways |
| title_sort | multivalent co assembly of ll37 cpg nanoparticles enhanced immune response through activating multiple cell internalization pathways |
| topic | Single-stranded nucleic acids Self-assembled nanoparticle LL37 Immune regulation Cell internalization |
| url | http://www.sciencedirect.com/science/article/pii/S2590006425005812 |
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