Injectable Immunotherapeutic Hydrogel Containing RNA-Loaded Lipid Nanoparticles Reshapes Tumor Microenvironment for Pancreatic Cancer Therapy

Abstract

Pancreatic cancer immunotherapy is becoming a promising strategy for improving the survival rate of postsurgical patients. However, the low response rate to immunotherapy suggests a low number of antigen-specific T cells and a high number of immunosuppressive tumor-associated macrophages in the pancreatic tumor microenvironment. Herein, we developed an in situ injectable thermosensitive chitosan hydrogel loaded with lipid-immune regulatory factor 5 (IRF5) mRNA/C–C chemokine ligand 5 (CCL5) siRNA (LPR) nanoparticle complexes (LPR@CHG) that reprogram the antitumoral immune niche. The LPR@CHG hydrogel upregulates IRF5 and downregulates CCL5 secretion, which contribute to a significant increase in M1 phenotype macrophages. Tumor growth is controlled by effective M1 phenotype macrophage that initiate T cell-mediated immune responses. Overall, the LPR@CHG hydrogel is expected to be a meaningful immunotherapy platform that can reshape the immunosuppressive tumor microenvironment and improve the efficacy of current pancreatic immunotherapies while minimizing systemic toxicity.

Nanoarchitecture-Integrated Hydrogel Systems toward Therapeutic Applications

“…115 For several more effective paradigms, mRNA and resiquimod (R848)-laden lipid nanoparticles (HA-mRLNPs) and RNA-loaded lipid nanoparticles were recently developed to integrate with injectable hydrogel transformable hyaluronan dynamic hydrogel for pancreatic and durable cancer immunotherapy by Wang's group and Re's group. 116,117 Additionally, Qiao et al combined an oleandrin-loaded microsphere (OL-M) with a hydrogel to construct a dual controlled release nanoplatform for precisely controlling the output of oleandrin in situ in tumors. 118 Particularly, an in situ sprayed bioresponsive immunotherapeutic gel was reported for tumor treatment.…”

Nanobiotechnology-Enabled mRNA Stabilization

“…Hydrogels also have potential in maintaining stability under physiological conditions. For example, hydrogels formed by chitosan remained stable (no swelling) under body fluid from tumor microenvironment treatment (Kras pancreatic cell-conditioned medium and leukemia cells in mouse macrophage-conditioned medium) for 28 days, making them a stable carrier for sustained mRNA-LNP release [ 69 ].…”

Transforming Cold Tumors into Hot Ones with a Metal–Organic Framework-Based Biomimetic Nanosystem for Enhanced Immunotherapy

“…Recently, innovative tumor immunotherapy has generated remarkable clinical successes by harnessing cytotoxic T lymphocytes (CTLs) within the immune system. , However, only ∼20% of patients with solid tumors benefit from this immuno-oncotherapy, which is attributed to the tumor microenvironment (TME) in “cold” tumors being relatively sparsely infiltrated with CTLs. − “Hot” tumors, characterized by a higher infiltration of CTLs, were more sensitive to tumor immunotherapy due to stronger immunogenicity. , Therefore, transforming immunologically cold tumors into hot ones can be a valuable means of addressing the low response rate in tumor immunotherapy. The cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway suppresses tumors induced by DNA damage and activates the innate immune response, which is indispensable for antitumor immune responses. , During STING trafficking, cyclic GMP-AMP (cGAMP) can serve as a secondary messenger that contributes to the transcription of IRF3 and NF-κB, facilitating type I interferon (IFN) secretion .…”