M1-C-LNPs Can Serve as An Optimal Nanoplatform for Effective Genetic Immunotherapy of Solid Tumors

Cancer remains the leading cause of death worldwide, and traditional treatment modalities such as chemotherapy and radiotherapy are often associated with recurrence risk and severe side effects. Gene therapy for cancer has gained increasing prominence due to its personalized capabilities. However, in order to effectively treat cancer through gene therapy, it is crucial to accurately target tumor cells, deliver tumor suppressor genes, or disrupt oncogenes using tools such as RNAi or CRISPR, as imprecise targeting may increase the risk of recurrence. Recent advances have shown that lipid nanoparticles (LNPs) are powerful carriers of siRNA therapies, showing potential in the management of genetic diseases.

Cancer immunotherapy, which focuses on mobilizing the body's own immune system to recognize and eradicate cancer cells, includes checkpoint blocking antibodies and chimeric antigen receptor (CAR) immune cell therapies, which have entered clinical application and shown encouraging potential in treating various tumor types. However, effective cancer immunotherapy is hampered by patient-specific and cancer-specific immunosuppressive tumor microenvironments (TMEs) as they suppress the activity of immune cells and prevent them from effectively targeting cancer cells. Intratumoral injection enhances the retention of these nanomedicines within tumors, more effectively stimulates the TME, and reduces systemic immune-related side effects, thus showing great promise in future clinical applications for cancer treatment.

The scientific community has been actively investigating the potential benefits of immune cell-derived nanovesicles (NVs), especially in terms of enhancing the safety, functionality, and therapeutic efficacy of immunotherapy. In addition, the innovative application of immune cell membrane coatings on nanoparticles has emerged as a strategy aimed at expanding their therapeutic potential. Recent studies have highlighted that NVs derived from M1 macrophages are rich in pro-inflammatory cytokines and can effectively modulate the TME, showing their potential as effective cancer immunotherapeutic agents.

Recently, researchers from Sungkyunkwan University in South Korea published an article titled "M1-polarized macrophage-derived cellular nanovesicle-coated lipid nanoparticles for enhanced cancer treatment through hybridization of gene therapy and cancer immunotherapy" in the journal Acta Pharm Sin B. The study showed that M1-C-LNPs can serve as an optimal nanoplatform for effective genetic immunotherapy of solid tumors, providing a promising strategy for developing targeted and effective nanoparticle-based cancer genetic immunotherapy.

Optimal genetic delivery of regulated target genes to diseased tissues is a major obstacle to achieving gene therapy. LNPs are considered a promising nucleic acid delivery vehicle and have been shown to be effective in humans during the COVID-19 pandemic. This study introduces a new biomaterial-based platform, dual-functionalized M1 macrophage-derived cellular nanovesicle-coated lipid nanoparticles (M1-C-LNPs), specifically for combined gene-immunotherapy approaches against solid tumors. This study developed bifunctional M1-C-LNPs containing Bcl2-siRNA and immunomodulatory cytokines to combine gene therapy and immunotherapy for cancer treatment.

Figure 1. Schematic of the M1-C-LNPs for efficient cancer therapy in the tumor microenvironment. (Shin H E, et al., 2024)

M1-CLNPs successfully integrated the properties of LNPs coated with siRNA and M1-NVs enriched with inflammatory cytokines through an extrusion process. The siRNA loaded on M1-C-LNPs was specifically delivered to cancer cells and induced cell death only in cancer cells without affecting immune cells in the tumor microenvironment, such as effector immune cells. However, the inflammatory cytokines in M1-C-LNPs stimulated T cells and NK cells, activating the particle-mediated cancer cell killing function.

Intratumoral injection of M1-C-LNPs showed good intratumoral retention due to the adhesion molecules on the surface of M1-NVs, which contributed to the therapeutic efficacy and safety of the nanoparticles. Ultimately, M1-C-LNPs showed superior efficacy in inhibiting tumor growth compared with other groups. These findings suggest that M1-C-LNPs can serve as an optimal nanoplatform for effective genetic immunotherapy of solid tumors.