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Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
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Dual-Action Protein-siRNA Conjugates for Targeted Disruption of CD47-Signal Regulatory Protein α Axis in Cancer

Jong Won Lee1,2, Hong Yeol Yoon2,3, Young Ji Ko2

  • 1KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.

ACS Nano
|August 8, 2024
PubMed

Insights

New RNA therapeutics use a dual-action conjugate to deliver RNA interference (RNAi) beyond liver cells. This approach disrupts the CD47/SIRPα axis, enhancing cancer immunotherapy for solid tumors.

Area of Science:

  • Biotechnology
  • Immunology
  • Oncology

Background:

  • RNA interference (RNAi) therapies have shown success in liver diseases.
  • Current RNAi delivery methods are limited, primarily to hepatocytes.
  • Alternative strategies are needed to expand RNAi applications to solid tumors.

Purpose of the Study:

  • To develop novel RNA delivery systems for solid tumors.
  • To investigate the efficacy of SIRPα IgV/anti-CD47 siRNA (vS-siCD47) conjugates.
  • To overcome the CD47/SIRPα-mediated "don't eat me" signal in cancer immunotherapy.

Main Methods:

  • Conjugation of SIRPα IgV domain protein to anti-CD47 siRNAs.
  • Utilizing the conjugate for tumor penetration via CD47-mediated erythrocyte piggybacking.
  • Internalization of conjugates into cancer cells, followed by siRNA-mediated CD47 silencing.
  • Assessing phagocyte-mediated tumor destruction.

Main Results:

  • vS-siCD47 conjugates selectively and persistently disrupt the CD47/SIRPα axis in solid tumors.
  • The dual-action approach overcomes the "don't eat me" barrier.
  • Phagocyte-mediated tumor destruction is stimulated, demonstrating potent CD47-blocking immunotherapy.
  • The strategy enables tumor 'dash through' via CD47-mediated erythrocyte piggybacking.

Conclusions:

  • IgV domain protein-siRNA conjugates offer a promising dual-action delivery strategy for RNAi.
  • This approach holds potential for expanding RNAi applications beyond hepatocytes.
  • The technology advances RNAi-based cancer immunotherapies for solid tumors.
Keywords:
RBC-hitchhikingRNA interferencecancer immunotherapyprotein−RNA bioconjugatesiRNA delivery

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