“Emerging precision drug delivery systems for controlled activation of the cGAS–STING pathway in Cancer, infection, and autoimmune disorders”

Dec 19, 2025International immunopharmacology

New targeted drug delivery methods for controlled activation of the immune sensing pathway in cancer, infections, and autoimmune diseases

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Abstract

The cGAS-STING pathway plays a critical role in innate immunity by detecting cytosolic DNA and initiating type I interferon responses.

STING is a potential therapeutic target for conditions such as cancer, infectious diseases, neuroinflammation, and autoimmune disorders.
Challenges in clinical application of STING modulators include poor drug absorption, rapid clearance from the body, and unintended immune responses.
Various delivery technologies, including lipid nanoparticles and polymeric carriers, have been developed to enhance the effectiveness of STING therapies.
Innovative approaches, such as stimuli-responsive systems and mRNA encoded modulators, could enable more precise and adaptable targeting of the cGAS-STING pathway.
The review discusses the mechanisms and immunological effects of these delivery platforms, along with their clinical development status.

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The cyclic GMP-AMP synthase Stimulator of Interferon Genes (cGAS-STING) pathway is a key component of innate immunity, detecting cytosolic DNA and initiating type I interferon (IFN-I) responses that shape downstream adaptive immunity. Owing to its central role in antiviral defense, tumor immunosurveillance, and inflammatory regulation, STING has emerged as a promising therapeutic target across oncology, infectious diseases, neuroinflammation, and autoimmune disorders. However, the clinical translation of STING agonists and antagonists is constrained by poor pharmacokinetics, rapid systemic clearance, off-target cytokine release, and inefficient cytosolic delivery. To address these barriers, a diverse set of delivery technologies including lipid nanoparticles, polymeric carriers, inorganic nanomaterials, hydrogels, biologically derived vectors, and antibody STING conjugates has been developed to improve selective uptake, endosomal escape, pHarmacological stability, and tissue-specific accumulation. This review systematically examines these platforms, highlighting their mechanisms, immunological effects, advantages, limitations, and stages of clinical progression. Emerging innovations such as stimuli-responsive delivery systems, mRNA encoded STING modulators, virus-like particle (VLP) technologies, carrier-free nanocomplexes, and cell-based delivery approaches are also discussed for their potential to enable precise, tunable, and context-specific modulation of the cGAS-STING axis. Collectively, these advances represent a significant evolution in STING-targeted therapy, providing new opportunities to harness innate immunity and expand therapeutic applications across a broad spectrum of disease settings.

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“Emerging precision drug delivery systems for controlled activation of the cGAS–STING pathway in Cancer, infection, and autoimmune disorders”

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