Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy

Abstract

Therapeutic cancer vaccines require adjuvants leading to robust type I interferon and proinflammatory cytokine responses in the tumor microenvironment to induce an anti-tumor response. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. However, their efficacy may be limited to micromolar concentrations due to the cytosolic residence of STING in the ER membrane. Here we utilized biodegradable, poly(beta-amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro. The leading CDN PBAE nanoparticle formulation induced a log-fold improvement in potency in treating established B16 melanoma tumors in vivo when combined with PD-1 blocking antibody in comparison to free CDN without nanoparticles. This nanoparticle-mediated cytosolic delivery method for STING agonists synergizes with checkpoint inhibitors and has strong potential for enhanced cancer immunotherapy.

Viromimetic STING Agonist‐Loaded Hollow Polymeric Nanoparticles for Safe and Effective Vaccination against Middle East Respiratory Syndrome Coronavirus

“…The safety concern regarding adjuvant reactogenicity has motivated ongoing development of particulate adjuvant formulations, which have been designed to target the lymphatic system to better promote localized immune responses. For the CDN‐based, STING agonist adjuvant adopted in the present study, several vehicles, including liposomes,9a,36 calcium phosphate nanoparticles, polymeric microparticles, and cationic polymers, have been applied to improve the molecule's potency and safety in prior reports. Compared to the aforementioned STING agonist formulations, the hollow polymeric nanoparticle developed herein possesses the combined advantages of biocompatibility, size consistency, colloidal stability, tunable adjuvant loading, pH‐responsive release, and antigen functionalizability.…”

Cancer‐Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery

“…Differences in size and physical properties among nucleic acids can also affect loading and binding. For instance, CDNs, siRNA, and miRNA are much smaller than plasmid DNA and thus have fewer binding sites per molecule for electrostatic complexation, and this reduced multivalency can reduce binding affinity . On the other hand, smaller cargos may be more amenable to chemical conjugation to nanoparticles.…”

“…While PBAEs, like other cationic polymers that form electrostatic complexes, bind to oligonucleotides less efficiently than to larger plasmids due to reduced avidity, the relatively low toxicity of PBAEs permits the use of higher amounts of the polymer or branched polymer structures with greater amine density to compensate for lower binding affinity. Using these strategies, these biomaterials have been shown to be effective for delivery of short sequences like siRNA, miRNA, and CDNs . A recent report by Lopez‐Bertoni et al used disulfide‐containing PBAEs to codeliver miR‐148a and miR‐296‐5p, both miRNAs that inhibit the stem cell‐like phenotype of human glioblastoma (GBM) cells in an effort to prevent tumor growth in a mouse model .…”

Agonists and inhibitors of the STING pathway: Potential agents for immunotherapy

“…The 2′,3′‐cGAMP‐loaded PC7A NPs efficiently inhibited the replication of HIV RNA and generated a long‐lasting antiretroviral response in human peripheral blood mononuclear cells, with free cGAMP as a control. Other polymers, such as dextran microparticles and poly (beta‐amino ester) (PBAE) NPs, were also employed to deliver CDNs and achieved prominent effects.…”