Nanoparticle Encapsulation of Synergistic Immune Agonists Enables Systemic Codelivery to Tumor Sites and IFNβ-Driven Antitumor Immunity

Abstract

Effective cancer immunotherapy depends on the robust activation of tumor-specific antigen-presenting cells (APC). Immune agonists encapsulated within nanoparticles (NP) can be delivered to tumor sites to generate powerful antitumor immune responses with minimal off-target dissemination. Systemic delivery enables widespread access to the microvasculature and draining to the APC-rich perivasculature. We developed an immuno-nanoparticle (immuno-NP) coloaded with cyclic diguanylate monophosphate, an agonist of the stimulator of interferon genes pathway, and monophosphoryl lipid A, and a Toll-like receptor 4 agonist, which synergize to produce high levels of type I IFNb. Using a murine model of metastatic triple-negative breast cancer, systemic delivery of these immuno-NPs resulted in significant therapeutic outcomes due to extensive upregulation of APCs and natural killer cells in the blood and tumor compared with control treatments. These results indicate that NPs can facilitate systemic delivery of multiple immunepotentiating cargoes for effective APC-driven local and systemic antitumor immunity.Significance: Systemic administration of an immunonanoparticle in a murine breast tumor model drives a robust tumor site-specific APC response by delivering two synergistic immune-potentiating molecules, highlighting the potential of nanoparticles for immunotherapy.

Macrophage imaging and subset analysis using single-cell RNA sequencing

“…In addition to the cytotoxic payload, TAM can release nanoparticles themselves after initial uptake, thus promoting subsequent delivery to neighboring tumor cells [165]. The uptake of nanoparticles by phagocytes has also been used to affect neighboring cells by stimulating phagocyte production of cytokines [93], chemoattractants [166][167], or vaccine-targeted antigens [168]. In other cases, phagocyte uptake may lead to unwanted drug sequestration or systemic clearance, and studies have shown how depleting MΦ [162], or saturating their ability to take up materials such as nanoparticles [169][170][171], can improve on-target delivery.…”

Emerging nanomedicines for effective breast cancer immunotherapy

“…As a result, tumor growth is suppressed and secondary tumor formation is inhibited in the PD-L1-insensitive mouse models of TNBC [61]. To further boost immune activity in tumor, both STING agonist cyclic diguanylate monophosphate and TLR4 agonist monophosphoryl lipid A were loaded into liposomes, followed by further modification of the liposomes with polyethylene glycol to improve solubility [62]. Systemic application of these developed liposomes increases the number of APCs and natural killer (NK) cells in the blood and tumor, leading to significant inhibition of tumor growth and metastasis in a murine model of metastatic TNBC [62].…”

“…To further boost immune activity in tumor, both STING agonist cyclic diguanylate monophosphate and TLR4 agonist monophosphoryl lipid A were loaded into liposomes, followed by further modification of the liposomes with polyethylene glycol to improve solubility [62]. Systemic application of these developed liposomes increases the number of APCs and natural killer (NK) cells in the blood and tumor, leading to significant inhibition of tumor growth and metastasis in a murine model of metastatic TNBC [62]. Similar to STING, retinoic acid-inducible gene I (RIG-I) is also a pattern recognition receptor, which is activated by viral RNAs.…”

Improving STING Agonist Delivery for Cancer Immunotherapy Using Biodegradable Mesoporous Silica Nanoparticles

“…In summary, we have developed bMSN for efficient cytosolic delivery of STING agonists. While previous studies have reported various STING agonist‐loaded NP systems, [ 10,11,28–30 ] including liposomes and polymeric NPs, their fabrication and drug loading procedures are often complicated with multiple synthesis and separation steps, and many of these NP platforms have not been clinically tested. On the other hand, silica‐based NPs offer a promising platform with biocompatibility, facile manufacturing process, and clinical safety.…”