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Polyelectrolyte nanoparticles enable intracellular delivery of STING protein fragments for ovarian cancer
Justin A Kaskow1,2, Altaf Bacchus1, Victoria F Gomerdinger1,2,3
1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Abstract:
Therapeutic activation of stimulator of interferon genes (STING) signaling shows promise as a method of inflaming the tumor microenvironment to generate an anti-cancer immune response. Frequent loss of STING expression in many human cancers renders small-molecule agonists ineffective in cancer cells. We previously demonstrated that delivering a fragment of the STING protein, dubbed STINGΔTM, to the cytosol can bypass this challenge by directly activating downstream signaling molecules in the cytosol; however, this strategy requires an effective cytosolic protein delivery vehicle to be therapeutically active. In this work, we develop a poly(β-amino ester) (PBAE) degradable polycation nanoparticle formulation to target ovarian cancer and deliver bioactive STINGΔTM protein to the cytosol. Screening experiments reveal that increasing PBAE hydrophobicity enables efficient protein encapsulation and delivery to the cytosol. We then develop a pH-shift-mediated method to assemble smaller, negatively charged nanoparticles composed of STINGΔTM protein, PBAE, and a polyanion. The polyanion can tune the cell type specificity of STING signaling activation in vitro, with poly(L-glutamate) and poly(L-aspartate) preferentially activating signaling in ovarian cancer cells. In a syngeneic mouse model of ovarian cancer, nanoparticles accumulate preferentially in tumors throughout the abdomen, slow tumor growth, and extend survival. Overall, the development of a tumor-targeted PBAE nanoparticle enabled the treatment of ovarian cancer through the direct intracellular delivery of STING protein, yielding an immunotherapy that shows promise for the treatment of cancers with dysregulated STING.
Insights
This study developed targeted nanoparticles to deliver STING protein directly into ovarian cancer cells, bypassing common expression loss and activating anti-cancer immunity. This novel immunotherapy approach shows promise for treating STING-dysregulated cancers.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
- Biochemistry
Background:
- Stimulator of interferon genes (STING) pathway activation is a promising strategy for cancer immunotherapy by inflaming the tumor microenvironment.
- Loss of STING expression in many cancers limits the efficacy of small-molecule agonists.
- Direct cytosolic delivery of STING protein fragments (STINGΔTM) can bypass STING expression loss and activate downstream signaling.
Purpose of the Study:
- To develop a targeted nanoparticle delivery system for bioactive STINGΔTM protein to the cytosol of ovarian cancer cells.
- To investigate the potential of this STING-based immunotherapy for treating ovarian cancer, particularly in cases with dysregulated STING.
Main Methods:
- Development of poly(β-amino ester) (PBAE) degradable polycation nanoparticles for targeted delivery of STINGΔTM protein.
- Optimization of PBAE hydrophobicity for efficient protein encapsulation and cytosolic delivery.
- Assembly of pH-shift-mediated nanoparticles using STINGΔTM, PBAE, and polyanions (poly(L-glutamate), poly(L-aspartate)) for targeted STING activation in ovarian cancer cells.
- Evaluation of nanoparticle efficacy in a syngeneic mouse model of ovarian cancer.
Main Results:
- Increasing PBAE hydrophobicity enhanced protein encapsulation and cytosolic delivery.
- Polyanions tuned STING signaling activation, with poly(L-glutamate) and poly(L-aspartate) showing preferential activation in ovarian cancer cells.
- Targeted nanoparticles accumulated in abdominal tumors, slowed tumor growth, and extended survival in a mouse model.
- Direct intracellular delivery of STING protein via PBAE nanoparticles demonstrated therapeutic potential.
Conclusions:
- A tumor-targeted PBAE nanoparticle system effectively delivered STINGΔTM protein to the cytosol of ovarian cancer cells.
- This approach bypasses STING expression loss and elicits an anti-cancer immune response, showing promise for treating STING-dysregulated cancers.
- The developed nanoparticle-mediated immunotherapy represents a novel strategy for ovarian cancer treatment.
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