Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE)

Parhiz, Hamideh; Brenner, J.; Patel, Priyal; Papp, Tyler E.; Shahnawaz, Hamna; Qin, Li; Shi, Ruiqi; Zamora, Marco; Yadegari, Amir; Marcos‐Contreras, Oscar A.; Natesan, Ambika; Pardi, Norbert; Shuvaev, Vladimir V.; Kiseleva, Raisa; Myerson, Jacob W.; Uhler, Thomas; Riley, Rachel; Han, Xuexiang; Mitchell, Michael J.; Lam, Kieu; Heyes, James; Weissman, Drew; Muzykantov, Vladimir R.

doi:10.1016/j.jconrel.2021.12.027

Cited by 65 publications

(53 citation statements)

References 72 publications

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“…Thus, LNP and mRNA-LNP can likely directly or indirectly engage receptors to induce interferons [ 4 , 7 ] and reduce subsequent mRNA translation. Pre-exposure to TLR4 ligand significantly decreased RNA translation from mRNA-LNP [ 32 , 33 ]. Altogether these data suggest that the mRNA-LNP platform efficiency might be influenced by pre-exposure to vaccines engaging the TLR/interferon pathways or by pre-existing inflammatory environments such as autoimmune disease or ongoing infections.…”

Section: Discussionmentioning

confidence: 99%

Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion

et al. 2022

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Hundreds of millions of SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. However, we lack a comprehensive understanding of the immune effects of this platform. The mRNA-LNP-based SARS-CoV-2 vaccine is highly inflammatory, and its synthetic ionizable lipid component responsible for the induction of inflammation has a long in vivo half-life. Since chronic inflammation can lead to immune exhaustion and non-responsiveness, we sought to determine the effects of pre-exposure to the mRNA-LNP on adaptive immune responses and innate immune fitness. We found that pre-exposure to mRNA-LNPs or LNP alone led to long-term inhibition of the adaptive immune response, which could be overcome using standard adjuvants. On the other hand, we report that after pre-exposure to mRNA-LNPs, the resistance of mice to heterologous infections with influenza virus increased while resistance to Candida albicans decreased. The diminished resistance to Candida albicans correlated with a general decrease in blood neutrophil percentages. Interestingly, mice pre-exposed to the mRNA-LNP platform can pass down the acquired immune traits to their offspring, providing better protection against influenza. In summary, the mRNA-LNP vaccine platform induces long-term unexpected immunological changes affecting both adaptive immune responses and heterologous protection against infections. Thus, our studies highlight the need for more research to determine this platform’s true impact on human health.

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Section: Discussionmentioning

confidence: 99%

Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion

et al. 2022

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“…The tumor microenvironment, which is largely orchestrated by inflammatory cells, fosters proliferation, survival and migration of neoplastic cells. Notably, inflammatory responses are aggravated on a background of pre-existing inflammatory conditions, as was recently demonstrated in a mouse model after administration of mRNA-LNPs [144]. This effect was proven to be specific to the LNPs, acting independently of the mRNA cargo.…”

Section: Introductionmentioning

confidence: 67%

Navigating Uncharted Waters: Could COVID-19 and/or Certain COVID-19 Vaccines Promote Malignancy?

Angues¹,

Bustos²

2022

Preprint

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Cancer is a complex dynamic disease that involves different biological capabilities including sustaining proliferative signaling, evading tumor suppression and immune surveillance, resisting cell death, enabling replicative immortality, reprogramming energy metabolism, inducing angiogenesis, and activating invasion and metastasis. Underlying these capabilities are genome instability, which expedites their acquisition, and inflammation, which fosters their function/s. Additionally, cancer exhibits another dimension of complexity: a heterogeneous repertoire of infiltrating and resident host cells, secreted factors, and extracellular matrix, known as the tumor microenvironment, that through a dynamic and reciprocal relationship with cancer cells supports immortality, local invasion, and metastatic dissemination. This staggering intricacy calls for some caution when advising all people with cancer (or a previous history of cancer) to receive the COVID-19 primary vaccine series plus additional booster doses. Moreover, because these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, safety, and the risk of interactions with anticancer therapies, which could reduce the efficacy and/or safety of either medical treatment. After reviewing the available literature, we are particularly concerned that COVID-19 vaccination may predispose some (stable) oncologic patients and survivors to cancer progression, recurrence and/or metastasis. This hypothesis is based on biological plausibility (i.e., induction of lymphopenia and inflammation; downregulation of ACE2 expression; activation of oncogenic cascades; sequestration of tumor suppressor proteins; suppression of type I IFN responses; dysregulation of the G4-RNA-protein binding system; unsilencing of LINE-1 retrotransposons; etc.) together with growing anecdotal evidence and reports filed to Vaccine Adverse Effects Report System (VAERS) suggesting that some cancer patients experienced disease exacerbation or recurrence following COVID-19 vaccination. In light of the above, we encourage the medical and scientific community to urgently evaluate the impact of COVID-19 vaccination on cancer biology, adjusting public health recommendations accordingly.

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“…In another research, Hamideh Parhiz and coworkers (2022) worked on the induction of the acute inflammatory responses via activation of LPS and transferred them intratracheally, 1mg kg −1 , or intravenously, via inflammatory models. Their findings revealed that the pretreatment with anti‐inflammatory drugs, such as corticosteroids, can moderately lessen IE response in mice.…”

Section: Sirna‐based Nanocarriers To Control Imdsmentioning

confidence: 99%

“…This highlights the significance of LNP‐mediated IE phenomena in gram‐negative bacterial inflammation. Still, the generalizability of using RNA‐LNPs in other forms against chronic or acute inflammation remains to be addressed (Parhiz et al, 2022).…”

Section: Sirna‐based Nanocarriers To Control Imdsmentioning

confidence: 99%

siRNA‐based nanotherapeutics as emerging modalities for immune‐mediated diseases: A preliminary review

Sargazi

Arshad

Ghamari

et al. 2022

Cell Biology International

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Immune-mediated diseases (IMDs) are chronic conditions that have an immunemediated etiology. Clinically, these diseases appear to be unrelated, but pathogenic pathways have been shown to connect them. While inflammation is a common occurrence in the body, it may either stimulate a favorable immune response to protect against harmful signals or cause illness by damaging cells and tissues. Nanomedicine has tremendous promise for regulating inflammation and treating IMIDs. Various nanoparticles coated with nanotherapeutics have been recently fabricated for effective targeted delivery to inflammatory tissues. RNA interference (RNAi) offers a tremendous genetic approach, particularly if traditional treatments are ineffective against IMDs. In cells, several signaling pathways can be suppressed by using RNAi, which blocks the expression of particular messenger RNAs. Using this molecular approach, the undesirable effects of anti-inflammatory medications can be reduced. Still, there are many problems with using short-interfering RNAs (siRNAs) to treat IMDs, including poor localization of the siRNAs in target tissues, unstable gene expression, and quick removal from the blood. Nanotherapeutics have been widely used in designing siRNA-based carriers because of the restricted therapy options for IMIDs. In this review, we have discussed recent trends in the fabrication of siRNA nanodelivery systems, including lipid-based siRNA nanocarriers, liposomes, and cationic lipids, stable nucleic acid-lipid particles, polymeric-based siRNA nanocarriers, polyethylenimine (PEI)-based nanosystems, chitosan-based nanoformulations, inorganic material-based siRNA nanocarriers, and hybrid-based delivery systems. We have also introduced novel siRNA-based nanocarriers to

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Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE)

Cited by 65 publications

References 72 publications

Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion

Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion

Navigating Uncharted Waters: Could COVID-19 and/or Certain COVID-19 Vaccines Promote Malignancy?

siRNA‐based nanotherapeutics as emerging modalities for immune‐mediated diseases: A preliminary review

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