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已发表论文
肌肉注射全反式维甲酸佐剂纳米疫苗可诱导对幽门螺杆菌的强效黏膜和全身免疫反应
Authors Xu J , Sun M, Wang N, Shi Y , Liu Y, Tan R, Zhou S, Guo G, Liu K
Received 30 July 2025
Accepted for publication 13 December 2025
Published 28 December 2025 Volume 2025:20 Pages 15847—15861
DOI https://doi.org/10.2147/IJN.S557242
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Eng San Thian
Junhua Xu, Min Sun, Ning Wang, Yun Shi, Yu Liu, Runqing Tan, Song Zhou, Gang Guo, Kaiyun Liu
Institute of Biopharmaceuticals, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
Correspondence: Kaiyun Liu, Email liukaiyun@wchscu.edu.cn Gang Guo, Email guogang7001@163.com
Purpose: Helicobacter pylori (H. pylori) infection, implicated in chronic gastritis, peptic ulcers, and gastric cancer, poses a significant global health burden exacerbated by increasing antibiotic resistance. Traditional intramuscular vaccines often yield limited mucosal immunity, necessitating the development of more effective vaccination strategies capable of robust mucosal and systemic responses. Here, we report a novel nanovaccine (RA-NVs) combining all-trans retinoic acid (RA) and recombinant urease subunit proteins (UreA/UreB), encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles to enhance protective immunity against H. pylori.
Methods: RA-NVs were synthesized via single emulsion–diffusion–evaporation, with antigens loaded onto the nanoparticle surfaces. Their physicochemical properties, antigen loading capacity, and stability were characterized. In vitro dendritic cell (DC) activation, antigen uptake, and gut-homing receptor expression (C-C chemokine receptor 9, CCR9) were assessed. In vivo distribution was examined using in vivo imaging system (IVIS). BALB/c mice were immunized intramuscularly, and subsequent mucosal (IgA) and systemic (IgG) antibody responses, cytokine profiles, T cell proliferation, and bacterial clearance upon H. pylori challenge were evaluated. Vaccine biosafety was assessed via histopathological and biochemical analyses.
Results: RA-NVs exhibited optimal size, surface charge, and sustained antigen and RA release. In vitro assays demonstrated efficient DC uptake, enhanced CCR9 expression, cytokine secretion (IL-6, IL-10, IL-15), and improved DC migration towards C-C motif chemokine ligand 25 (CCL25). In vivo, RA-NVs significantly elevated serum IgG and mucosal IgA antibodies, promoted CD4+ and CD8+ T cell activation, and elicited robust Th2/Th17-skewed responses. Notably, immunized mice exhibited significantly reduced gastric bacterial colonization and inflammation upon H. pylori challenge, alongside excellent safety profiles with minimal toxicity and organ damage.
Conclusion: The RA-adjuvanted nanovaccine effectively induces potent mucosal and systemic immunity via intramuscular administration, representing a promising strategy against mucosal pathogens such as H. pylori. This nanovaccine platform addresses key limitations associated with oral vaccination and with conventional intramuscular approaches that often yield limited mucosal immunity, offering an alternative for enhancing mucosal vaccine efficacy in mice; although a direct head-to-head comparison with an oral formulation remains to be established.
Plain Language Summary: Helicobacter pylori (H. pylori) is a bacterium that infects the stomach lining and can lead to serious health issues, including ulcers and even stomach cancer. Antibiotics have been used to treat this infection, but they are becoming less effective due to growing antibiotic resistance. A vaccine that triggers a strong immune response in both the blood and the gut could provide better protection.
In this study, our research team designed a new vaccine called RA-NVs. It is made of nanoparticles containing vitamin A derivative (retinoic acid) and two antigens from H. pylori. Unlike traditional vaccines, these nanoparticles help immune cells find their way specifically to the gut, the main site where the bacteria cause damage.
When we tested this vaccine in mice, we found it effectively activated the immune system, producing antibodies that protect the stomach lining. Mice that received our vaccine had significantly fewer bacteria in their stomachs after exposure to H. pylori and showed much less stomach inflammation. We also confirmed that the vaccine is safe and did not harm vital organs.
Our results suggest this new vaccine is a promising tool to prevent stomach infections caused by H. pylori. This approach might also be useful for developing vaccines against other infections that affect mucosal surfaces, like those in the gut or respiratory tract.
Keywords: Helicobacter pylori, nanovaccine, all-trans retinoic acid, mucosal immunity, intramuscular delivery
Institute of Biopharmaceuticals, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China
Correspondence: Kaiyun Liu, Email liukaiyun@wchscu.edu.cn Gang Guo, Email guogang7001@163.com
Purpose: Helicobacter pylori (H. pylori) infection, implicated in chronic gastritis, peptic ulcers, and gastric cancer, poses a significant global health burden exacerbated by increasing antibiotic resistance. Traditional intramuscular vaccines often yield limited mucosal immunity, necessitating the development of more effective vaccination strategies capable of robust mucosal and systemic responses. Here, we report a novel nanovaccine (RA-NVs) combining all-trans retinoic acid (RA) and recombinant urease subunit proteins (UreA/UreB), encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles to enhance protective immunity against H. pylori.
Methods: RA-NVs were synthesized via single emulsion–diffusion–evaporation, with antigens loaded onto the nanoparticle surfaces. Their physicochemical properties, antigen loading capacity, and stability were characterized. In vitro dendritic cell (DC) activation, antigen uptake, and gut-homing receptor expression (C-C chemokine receptor 9, CCR9) were assessed. In vivo distribution was examined using in vivo imaging system (IVIS). BALB/c mice were immunized intramuscularly, and subsequent mucosal (IgA) and systemic (IgG) antibody responses, cytokine profiles, T cell proliferation, and bacterial clearance upon H. pylori challenge were evaluated. Vaccine biosafety was assessed via histopathological and biochemical analyses.
Results: RA-NVs exhibited optimal size, surface charge, and sustained antigen and RA release. In vitro assays demonstrated efficient DC uptake, enhanced CCR9 expression, cytokine secretion (IL-6, IL-10, IL-15), and improved DC migration towards C-C motif chemokine ligand 25 (CCL25). In vivo, RA-NVs significantly elevated serum IgG and mucosal IgA antibodies, promoted CD4+ and CD8+ T cell activation, and elicited robust Th2/Th17-skewed responses. Notably, immunized mice exhibited significantly reduced gastric bacterial colonization and inflammation upon H. pylori challenge, alongside excellent safety profiles with minimal toxicity and organ damage.
Conclusion: The RA-adjuvanted nanovaccine effectively induces potent mucosal and systemic immunity via intramuscular administration, representing a promising strategy against mucosal pathogens such as H. pylori. This nanovaccine platform addresses key limitations associated with oral vaccination and with conventional intramuscular approaches that often yield limited mucosal immunity, offering an alternative for enhancing mucosal vaccine efficacy in mice; although a direct head-to-head comparison with an oral formulation remains to be established.
Plain Language Summary: Helicobacter pylori (H. pylori) is a bacterium that infects the stomach lining and can lead to serious health issues, including ulcers and even stomach cancer. Antibiotics have been used to treat this infection, but they are becoming less effective due to growing antibiotic resistance. A vaccine that triggers a strong immune response in both the blood and the gut could provide better protection.
In this study, our research team designed a new vaccine called RA-NVs. It is made of nanoparticles containing vitamin A derivative (retinoic acid) and two antigens from H. pylori. Unlike traditional vaccines, these nanoparticles help immune cells find their way specifically to the gut, the main site where the bacteria cause damage.
When we tested this vaccine in mice, we found it effectively activated the immune system, producing antibodies that protect the stomach lining. Mice that received our vaccine had significantly fewer bacteria in their stomachs after exposure to H. pylori and showed much less stomach inflammation. We also confirmed that the vaccine is safe and did not harm vital organs.
Our results suggest this new vaccine is a promising tool to prevent stomach infections caused by H. pylori. This approach might also be useful for developing vaccines against other infections that affect mucosal surfaces, like those in the gut or respiratory tract.
Keywords: Helicobacter pylori, nanovaccine, all-trans retinoic acid, mucosal immunity, intramuscular delivery