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Published on: February 1, 2019
Improvement of Therapeutic Effect via Inducing Non-Apoptotic Cell Death Using mRNA-Protection Nanocage
Seoyoung Kim1, Seongchan Kim1,2,3, Sojin Kim4,5
1Biomaterial Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
Abstract:
Necroptosis, a cell death mechanism with the characteristics of both apoptosis and necrosis, is proposed as a promising therapeutic approach for cancer therapy. Induction of necroptosis for cancer therapy may be possible through the regulation of the expression of a key factor gene receptor-interacting protein kinase-3 (RIPK3) via in vitro transcription (IVT) mRNA delivery. However, mRNA is susceptible to degradation and has a low delivery efficiency, which highlights the requirement of a proper delivery vehicle for intracellular delivery. Therefore, a new mRNA delivery system based on the nanostructured silica nanoparticles, termed mRNA-protective nanocage (mPN) has been developed. High-efficiency expression of RIPK3 and induction of necroptosis is achieved through delivery of RIPK3 IVT mRNA with mPN in vitro and in vivo models. Importantly, the mPN carrying RIPK3 mRNA distributed locally in tumors upon intravascular injection, and successfully induced necroptosis and immune cell infiltration, a hallmark of necroptosis. the suppression of tumor growth in a murine cancer model, demonstrating the synergistic effect of RIPK3 mRNA- and immune cell-mediated therapy is also observed. These findings suggest the potential for anticancer therapy through necroptosis induction and provide a strategy for the development of mRNA-based nanomedicine.
Insights
This study introduces mRNA-protective nanocages (mPN) for delivering RIPK3 mRNA to induce necroptosis, a programmed cell death, for cancer therapy. This novel nanomedicine approach effectively suppresses tumor growth by combining RIPK3 induction with immune cell activation.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Cancer Biology
Background:
- Necroptosis, a regulated form of necrosis, is a promising cancer therapy target.
- Receptor-interacting protein kinase-3 (RIPK3) is a key factor in necroptosis induction.
- Current mRNA delivery methods face challenges with degradation and low efficiency.
Purpose of the Study:
- To develop an effective mRNA delivery system for cancer therapy.
- To investigate the potential of RIPK3 mRNA delivery via nanocarriers for necroptosis induction.
- To evaluate the therapeutic efficacy of this approach in preclinical cancer models.
Main Methods:
- Development of mRNA-protective nanocages (mPN) using nanostructured silica nanoparticles.
- Delivery of in vitro transcribed (IVT) RIPK3 mRNA using mPN in vitro and in vivo.
- Assessment of RIPK3 expression, necroptosis induction, immune cell infiltration, and tumor growth suppression.
Main Results:
- High-efficiency RIPK3 expression and necroptosis induction were achieved using mPN.
- mPN effectively delivered RIPK3 mRNA to tumors, inducing necroptosis and immune cell infiltration.
- Significant suppression of tumor growth was observed in a murine cancer model, indicating synergistic effects.
Conclusions:
- mRNA-protective nanocages (mPN) offer a viable strategy for delivering RIPK3 mRNA to induce necroptosis for cancer therapy.
- This nanomedicine approach demonstrates potential for synergistic anticancer effects by combining direct tumor cell death with immune stimulation.
- The findings support the development of mRNA-based nanomedicines for advanced cancer treatment.
