Loading of STING Agonist into Lipid Nanoparticles Boosts Dendritic Cell Activation

Sep 29, 2026

Activation of the STING pathway is crucial for antitumor immunity, yet delivering STING agonists into cells efficiently remains a major therapeutic hurdle. This study evaluates FDA-approved lipid nanoparticles (LNPs), originally used in the Spikevax COVID-19 vaccine, as carriers to enhance uptake of a cGAMP analog (cGsAsMP) by dendritic cells (DCs). The LNPs are reproducible, scalable, and promote cytoplasmic release, leading to strong STING activation and DC maturation, including reprogramming tumor-associated DCs toward an active state. Overall, it presents a scalable LNP delivery strategy for cyclic dinucleotide STING agonists to counter cancer immune suppression.

LanguageEnglish

CategoryHealthcare

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Pages15

Reading Time38 min

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Abstract

Introduction

This article is licensed under CC-BY-NC-ND 4.0 [http://pubs.acs.org/journal/acsodf](http://pubs.acs.org/journal/acsodf) Article Loading of STING Agonist into Lipid Nanoparticles Boosts Dendritic Cell Activation Ana RS Ribeiro,‡ Ander Eguskiza,‡ Hieu-Hoa Dang, Theresa Neuper, Michael Stefan Unger, Laura Rodriguez Comas, Markus Steiner, Helene Sieberer, Nadja Zaborsky, Richard Greil, Mireia Vilar I Hernandez, Pascal Jonkheijm,* Roberto Fiammengo, * and Jutta Horejs-Hoeck* Cite This: ACS Omega 2025, 10, 58465−58479 Read Online | | | | | | | | --- | --- | --- | --- | --- | --- | | ACCESS | Metrics & More | | Article Recommendations | | *sı Supporting Information | ABSTRACT: Activation of the STING pathway is crucial for antitumor immunity, but targeting the STING receptor therapeutically remains a challenge due to inefficient intracellular delivery of its agonists. Here, we explore the potential of FDA-approved lipid nanoparticles (LNPs), used in Spikevax COVID-19 vaccine, to increase the uptake of a cGAMP analog (cGsAsMP) to dendritic cells (DCs) and induce cell activation. These LNPs are highly reproducible, effectively encapsulate cGsAsMP, and are easily scalable. We show that cGsAsMPLNPs are efficiently internalized by DCs in vitro, and the cargo is released into the cytoplasm, which strongly enhances STING activation and DC maturation. Furthermore, we introduce an in vitro model of tumor-associated human DCs that mimics the DC phenotype observed in cancer patients. When applied to this model, cGsAsMP LNPs successfully reprogram tumorassociated DCs toward an active state, thus emphasizing their potential for cancer immunotherapy. Overall, this work presents a novel and scalable approach utilizing LNPs to deliver cyclic dinucleotide-based STING agonists to counteract immune suppression in cancer. 1. INTRODUCTION Current immunotherapy strategies concentrate on harnessing the host immune system to destroy tumor cells through robust adaptive antitumor responses, with notable success in the treatment of both solid and hematological malignancies tied to the deployment of immune checkpoint blockade and chimeric antigen receptor T cells (CAR-T), respectively.1,2 Nonetheless, the progress in activating tumor-specific T-cell responses alone has been slow because that activity depends on each patient’s immune context and, in particular, on signals received from innate immune cells, such as dendritic cells (DCs).3−5 DCs are specialized antigen-presenting cells (APCs) that, by surveilling and sampling all tissues, can recognize molecular patterns associated with pathogens (PAMPs) or cellular damage (DAMPs), thus prompting appropriate immune responsesand playing a key role in fighting diseases such as cancer.6 In the tumor context, DCs can sustain specific antitumor immune responses by activating cytotoxic CD8+ T cells and by priming CD4+ T cells.4,5,7 However, in the case of solid tumors, an immunosuppressive tumor microenvironment (TME) often develops, which contributes to immune evasion by severely compromising the functions of various immune cells, including DCs.8,9 Specifically at the DC level, there is evidence that the TME promotes the upregulation of immune checkpoint molecules, coinhibitory markers and immunosuppressive factors in cancer patients, resulting in regulatory T-cell polarization that prevents potent antitumor immunity.8, 10 In human blood, two major subsets of conventional dendritic cells (cDCs) are recognized: CD141+ cDC1 and CD1c+ cDC2.11 While cDC 1s are established as key mediators of antitumor immunity through efficient cross-priming of CD8+ T cells, 12 recent evidence highlights an equally important role for cDC 2s. Beyond presenting antigens to both CD4+ and CD8+ T cells, 13 cDC 2s can transfer tumorderived antigens to resident DCs in lymphoid tissues, thereby amplifying antitumor T cell responses.14 A critical signaling pathway in antitumor immunity involves the activation of

FAQs

Why is STING pathway activation important for antitumor immunity?

STING activation triggers inflammatory signaling that supports effective antitumor immune responses. It particularly helps promote cross-priming of CD8+ T cells via DC activation.

What problem does this work address in STING-targeted therapies?

Therapeutic targeting of STING is challenging because STING agonists are inefficiently delivered into cells. The study aims to improve intracellular delivery using lipid nanoparticles.

How do the lipid nanoparticles affect dendritic cells in this study?

The LNPs are efficiently internalized by dendritic cells in vitro and release the cargo into the cytoplasm. This strongly enhances STING activation and DC maturation, and it reprograms tumor-associated DCs toward an active state.

Sep 29, 2026

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