Hybrid LNP Prime Dendritic Cells for Nucleotide Delivery

Das, Riddha; Halabi, Elias A.; Fredrich, Ina R.; Oh, Juhyun; Peterson, Hannah M.; Ge, Xinying; Scott, Ella; Kohler, Rainer H.; Garris, Christopher S.; Weissleder, Ralph

doi:10.1002/advs.202303576

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…As expected, we observed a large induction of IL-12, a key effector cytokine in DCs [40‑43]. Naturally, we also observed induction of other cytokines and chemokine as would be expected with poly I:C and R848/Lcl161 delivery 31 . Importantly, we did not observe significant cytokine induction with the ferrocene-guanidine nanoparticle (CANDI610), indication that the Fe concentrations are not sufficient to induce ROS stimulation observed in other ferrocene polymers 44 .…”

Section: Discussionsupporting

confidence: 87%

“…There is emerging evidence that combination treatments 30 result in synergistic immunostimulation with higher immune responses at reduced drug concentration, reducing potential therapy side effects. While lipid nanoparticles have been used to deliver poly I:C and NFkB pathway modulators 31 , we reasoned that more stable, polymeric constructs would have practical, pharmacological, and biological advantages. Using bis-succinyl cyclodextrin as a versatile host-guest system, we first optimized linker chemistry and then grafted different components onto the nanoparticles ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

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A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation

Kim,

Halabi,

Enbergs

et al. 2024

Theranostics

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Rationale : Nucleic acid constructs are commonly used for vaccination, immune stimulation, and gene therapy, but their use in cancer still remains limited. One of the reasons is that systemic delivery to tumor-associated antigen-presenting cells (dendritic cells and macrophages) is often inefficient, while off-target nucleic acid-sensing immune pathways can stimulate systemic immune responses. Conversely, certain carbohydrate nanoparticles with small molecule payloads have been shown to target these cells efficiently in the tumor microenvironment. Yet, nucleic acid incorporation into such carbohydrate-based nanoparticles has proven challenging. Methods : We developed a novel approach using cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles to efficiently deliver nucleic acids and small-molecule immune enhancer to phagocytic cells in tumor environments and lymph nodes. Our study involved incorporating these components into the nanoparticles and assessing their efficacy in activating antigen-presenting cells. Results : The multi-modality immune stimulators effectively activated antigen-presenting cells and promoted anti-tumor immunity in vivo. This was evidenced by enhanced delivery to phagocytic cells and subsequent immune response activation in tumor environments and lymph nodes. Conclusion : Here, we describe a new approach to incorporating both nucleic acids and small-molecule immune enhancers into cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles for efficient delivery to phagocytic cells in tumor environments and lymph nodes in vivo. These multi-modality immune stimulators can activate antigen-presenting cells and foster anti-tumor immunity. We argue that this strategy can potentially be used to enhance anti-tumor efficacy.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation

Kim,

Halabi,

Enbergs

et al. 2024

Theranostics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Their combination with other immunotherapies (e.g., check-point inhibitors, chimeric antigen receptor (CAR) T cells, or oncolytic viruses) or with conventional cancer treatments (e.g., chemotherapy, irradiation) may improve the clinical outcome [1]. Moreover, DNA vaccines can be optimized by (i) the careful choice of suitable antigens, (ii) the selection of appropriate adjuvants to stimulate APCs [18][19][20][21][22][23][24], (iii) the use of efficient delivery systems (e.g., nanoparticles like polyplexes [25][26][27][28][29][30]), and (iv) the structural optimization of the DNA itself. The latter can be achieved by using a strong APC-specific promoter that confines tumor antigen expression to APC.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Targeting of Dendritic Cells Using an Optimized Human Fascin1 Gene Promoter

Zeyn,

Hobernik,

Wilk

et al. 2023

IJMS

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Deeper knowledge about the role of the tumor microenvironment (TME) in cancer development and progression has resulted in new strategies such as gene-based cancer immunotherapy. Whereas some approaches focus on the expression of tumoricidal genes within the TME, DNA-based vaccines are intended to be expressed in antigen-presenting cells (e.g., dendritic cells, DCs) in secondary lymphoid organs, which in turn induce anti-tumor T cell responses. Besides effective delivery systems and the requirement of appropriate adjuvants, DNA vaccines themselves need to be optimized regarding efficacy and selectivity. In this work, the concept of DC-focused transcriptional targeting was tested by applying a plasmid encoding for the luciferase reporter gene under the control of a derivative of the human fascin1 gene promoter (pFscnLuc), comprising the proximal core promoter fused to the normally more distantly located DC enhancer region. DC-focused activity of this reporter construct was confirmed in cell culture in comparison to a standard reporter vector encoding for luciferase under the control of the strong ubiquitously active cytomegalovirus promoter and enhancer (pCMVLuc). Both plasmids were also compared upon intravenous administration in mice. The organ- and cell type-specific expression profile of pFscnLuc versus pCMVLuc demonstrated favorable activity especially in the spleen as a central immune organ and within the spleen in DCs.

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Lipid Nanoparticle‐mRNA Engineered Dendritic Cell Based Adoptive Cell Therapy Enhances Cancer Immune Response

Das,

Ge,

Fei

et al. 2024

Small Methods

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Lipid nanoparticles encapsulating mRNA (LNP‐mRNA) revolutionized medicine over the past several years. While clinically approved indications currently focus on infectious disease vaccination, LNP‐mRNA based treatments also hold promise for cancer immunotherapy. However, the route of dosing may impact treatment efficacy, safety, and dose. To minimize adverse effects, it is hypothesized that LNP‐mRNA can be used to activate and engineer dendritic cells (DC) ex vivo before re‐administration of these cells. Here, it is shown that LNP‐mRNA engineered DCs can indeed vaccinate recipient mice. Vaccinated mice showed strong anti‐tumor T cell responses, rejected tumor challenge, and displayed no evidence of toxicity. Further, it is found that DC specific ablation of the immune activating kinase NFkB inducing kinase (NIK) abrogated vaccination efficacy, demonstrating that adoptively transferred DCs can be functionally modified in addition to their antigen presentation capacity. Collectively, these studies show that ex vivo LNP‐mRNA engineering of DCs is a feasible and robust therapeutic strategy for cancer.

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Hybrid LNP Prime Dendritic Cells for Nucleotide Delivery

Cited by 4 publications

References 37 publications

A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation

A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation

Transcriptional Targeting of Dendritic Cells Using an Optimized Human Fascin1 Gene Promoter

Lipid Nanoparticle‐mRNA Engineered Dendritic Cell Based Adoptive Cell Therapy Enhances Cancer Immune Response

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