Targeting intracellular and extracellular receptors with nano-to-macroscale biomaterials to activate immune cells

Bi, Wang; Cui, Hao; Kießling, Fabian; Lammers, Twan; Baumjohann, Dirk; Shi, Yang

doi:10.1016/j.jconrel.2023.03.028

Cited by 4 publications

(2 citation statements)

References 144 publications

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“…It has been demonstrated that mLNP-circRNA-G can induce potent and persistent immune responses, but one of the prerequisites of the wide application of circRNA vaccines is overcoming the challenge of long-term storage of mLNP-circRNA vaccines ( 39 ). We and others have demonstrated that using LNPs with targeting modifications to deliver mRNA to specific organs and cells can effectively improve the immune response ( 40 – 42 ). To determine whether the lyophilization process will affect the targeting modification of mLNPs and, thus, the immunogenicity, we lyophilized mLNP-circRNA-G and then stored the lyophilized mLNP-circRNA-G vaccine at 4°C for 24 weeks.…”

Section: Resultsmentioning

confidence: 99%

Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses

Wan,

Wang,

Wang

et al. 2024

mBio

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Several recent attempts to improve the stability and immunogenicity of messenger RNA (mRNA) vaccines include the use of circular RNA (circRNA), targeted delivery, and lyophilization. However, these research directions have often been pursued independently, ignoring the impact of the modification of lipid nanoparticle-encapsulated mRNA vaccines on their targeted delivery after lyophilization and on their subsequent immunogenicity. Here, we develop a circRNA vaccine targeting lymph nodes that expresses rabies virus glycoprotein (G), termed circRNA-G. Mannose modification is introduced directly into the process of synthesizing PEG lipids, and the resulting PEG-mannose can be used in the preparation of mannose-LNPs (mLNPs) that target dendritic cells, thereby promoting the specific distribution of circRNA-G to lymph nodes (mLNP-circRNA-G). We demonstrated that mLNP-circRNA-G has continuous antigen availability that promotes the generation of T follicular helper cells, germinal center B cells, long-lived plasma cells, and memory B cells in mice. Importantly, the vaccine with this targeting modification remained stable for at least 24 weeks of storage at 4℃ after lyophilization, and its immunogenicity was also maintained. Notably, this strategy also enhances the antibody production of the SARS-CoV-2 trimeric receptor-binding domain circRNA vaccine and the stability of immunogenicity after lyophilization. In summary, this study provides a general platform for the design of lyophilized vaccines with targeted stability, demonstrating the potential of lymph node-targeting circRNAs as next-generation vaccines. IMPORTANCE messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA and the nonspecificity of lipid nanoparticle-encapsulated (LNP) delivery systems result in the need for cold storage and a relatively short-duration immune response to mRNA vaccines. Herein, we develop a novel vaccine in the form of circRNAs encapsulated in LNPs, and the circular structure of the circRNAs enhances their stability. Lyophilization is considered the most effective method for the long-term preservation of RNA vaccines. However, this process may result in irreversible damage to the nanoparticles, particularly the potential disruption of targeting modifications on LNPs. During the selection of lymph node-targeting ligands, we found that LNPs modified with mannose maintained their physical properties almost unchanged after lyophilization. Additionally, the targeting specificity and immunogenicity remained unaffected. In contrast, even with the addition of cryoprotectants such as sucrose, the physical properties of LNPs were impaired, leading to an obvious decrease in immunogenicity. This may be attributed to the protective role of mannose on the surface of LNPs during lyophilization. Freshly prepared and lyophilized mLNP-circRNA vaccines elicited comparable immune responses in both the rabies virus model and the SARS-CoV-2 model. Our data demonstrated that mLNP-circRNA vaccines elicit robust immune responses while improving stability after lyophilization, with no compromise in tissue targeting specificity. Therefore, mannose-modified LNP-circRNA vaccines represent a promising vaccine design strategy.

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Section: Resultsmentioning

confidence: 99%

Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses

Wan,

Wang,

Wang

et al. 2024

mBio

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“…Many preclinical and clinical studies have demonstrated that conventional chemotherapeutic strategies induce cytotoxic effects and simultaneous activation of antitumor immune responses. − For example, cabazitaxel, a clinically approved next-generation taxane, overcomes taxane resistance in patients with docetaxel-refractory cancer and can repolarize tumor-associated macrophages (TAMs) from protumorigenic M2 to antitumorigenic M1, activating the downstream NF-κB. − Even though it is effective, the high toxicity of the cabazitaxel regimen limits its use in clinical oncology . Agonists of Toll-like receptors (TLRs) are candidate adjuvants for cancer immunotherapy. − Resiquimod, a TLR7/8 agonist, not only primes tumor-specific T-cell responses by stimulating APC maturation and T-cell proliferation but also engages in inducing the M1 phenotype. − However, uncontrolled continuous innate immune stimulation with TLR agonists leads to the exhaustion of APCs and T cells, resulting in suboptimal outcomes . In addition, rapid clearance from the circulation and unfavorable systemic dissemination, resulting from small-molecule administration, may compromise their biological activities and increase the likelihood of systemic adverse effects …”

Section: Introductionmentioning

confidence: 99%

Syringeable Near-Infrared Light-Activated In Situ Immunogenic Hydrogel Boosts the Cancer-Immunity Cycle to Enhance Anticancer Immunity

Fu,

Zhu,

Ren

et al. 2024

ACS Nano

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Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically “cold” tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer–drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.

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Biomaterials-mediated ligation of immune cell surface receptors for immunoengineering

Cui,

Zhang,

Shi

2024

Immuno-Oncology and Technology

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Targeting intracellular and extracellular receptors with nano-to-macroscale biomaterials to activate immune cells

Cited by 4 publications

References 144 publications

Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses

Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses

Syringeable Near-Infrared Light-Activated In Situ Immunogenic Hydrogel Boosts the Cancer-Immunity Cycle to Enhance Anticancer Immunity

Biomaterials-mediated ligation of immune cell surface receptors for immunoengineering

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