ENGINEERING IMMUNOMODULATORY CAPACITY OF LYMPH NODE-TARGETED DRUG DELIVERY CARRIERS

Abstract

Cancer metastasis and tumor-induced immune tolerance present major unresolved challenges in oncology, afflicting patients with systemic immunosuppression still unresolved by current therapies. A significant barrier to effective immunotherapy has been the inability to deliver potent immunomodulators directly to the secondary lymphoid organs, allowing tumors to suppress localized immune responses. This issue has proposed a critical need for enhanced drug delivery vehicles which target the LN.

To address the problem of poor drug delivery across biological barriers, previous research efforts have aimed to develop synthetic vehicles for targeted drug delivery. However, many of these technologies have issues such as off-target accumulation or rapid clearance from the blood, both of which reduce the success of drug delivery to the intended disease site. Advances in biomimetic or live cell-based carriers have improved targeted circulation but exist at the cost of adverse responses and batch-to-batch biological variability. Recently, a more promising “cryoshocking” approach has emerged, which lies on the foundation of subjecting immune cells to controlled necrosis to obtain a dead yet functionally targeted cell. The resulting dead cell capsule maintains an intact structure for drug encapsulation and functional targeting to the LN with removed pathogenicity.

Based on previous cryoshocking approaches, this study proposed the optimized development of cryoshocked T lymphocytes (CSTLs), alongside highly tunable synthetic alginate microparticles (MPs), for enhanced targeting and delivery of Stimulator of Interferon Genes (STING) agonists to the LN. This strategy leverages the unique targeting moieties expressed on the surface of T lymphocytes for improved LN entry, while simultaneously developing robust synthetic counterparts to physically shield highly vulnerable nucleotide-based payloads.

To optimize these vehicles for immunomodulation, T lymphocytes were first targeted for endogenous modifications prior to cryoshocking to enhance their innate immunogenicity. Concurrently, manufacturing protocols for synthetic alginate MPs were established to circumvent the biological variability inherent to cellular carriers. To then assess their utility as stable immunomodulatory carriers, vehicle loading capacities and in vivo functional efficacies were evaluated utilizing both nucleotide (cdi-GMP) and non-nucleotide (MSA-2) STING agonists.

Collectively, this research demonstrates the mechanical complexities of targeted immunomodulator delivery and highlights the limitations of the current biological CSTL model for single-agent STING agonist administration. While the in vivo outcomes of this study reveal distinct biochemical and physical payload barriers, they strongly support the transition toward robust, synthetic delivery platforms. It is believed that this technology will drastically improve the efficacy of localized cancer vaccines and overcome tumor-induced immune tolerance in the future.