Periodic Reporting for period 1 - NanoRNA_PC (Engineering the protein corona on RNA nanoparticles for improved nucleic acids-based therapies delivery)
Période du rapport: 2020-05-14 au 2022-05-13
In the past three decades, nanomedicine has emerged as a promising strategy in cancer treatment and has led to numerous proposed drug delivery systems. Nanoparticles aim to improve selectivity towards cancer cells while reducing off-target effects and toxicity towards normal cells. Among these systems, self-assembled RNA nanoparticles have been of great interest for drug delivery, because of their low cost, high yielding assembly and retained functionality. However, to propel these structures towards clinical applications, challenges such as poor nuclease resistance, biodistribution and cellular delivery need to be addressed. An important first step is to understand how they interact with biological components. In particular, upon injection, it is known that serum proteins bind to nanoparticles. The composition of this so-called protein-corona on RNA particles remains fully unexplored. Yet, the protein corona has been shown to dramatically influence biological outcomes of other types of nanoparticles (toxicity, or cellular uptake). Herein, we propose to characterise the protein corona on RNA nanoparticles, as well as understand the role of the corona on the fate of RNA structures. Overall, the project aims at providing tools and rules for rational engineering of the protein corona on RNA nanoparticles. The project also aims at improving fundamental understanding on nanoparticles for drug delivery.
Results overview: During this project, we established novel methodologies to systematically study and compare the protein corona of RNA nanoparticles. Our methods have now been routinely implemented in Sixfold’s screening pipeline. We demonstrate that by altering the PK/PD of RNA nanoparticles we can alter the identity of the protein corona. Interestingly, enhanced stability in vitro and distribution to non-hepatic tissue were observed upon administration in vivo, providing new avenues to the delivery of RNA therapeutics (normally stuck in hepatic tissues). More work will be conducted on proteomics methodologies, and how we can modulate the protein corona in more detail. In general, this project opened new avenues for nanoparticle delivery as well as provided first insight regarding the mechanisms of distribution of RNA nanoparticles.
Exploitation and dissemination: Throughout the project, the researcher presented results and delivered reports, was involved in discussions with different project partners and participated in IP generation within the company. The researcher was actively engaged in public outreach (including Falling Walls finalist 2020 & jury member 2021, OTS Outreach Committee, Young Researcher Science Communication webinar presenter and AAAS Skills for Resilient Researchers webinar speaker) and engagement (as well as participation in scientific conferences and societies, including the OTS General Meeting 2020 & 2021, MSCA Cancer Research event and DNA nanotechnology webinar). A peer-reviewed publication was generated following on from this work, and is available with open-access via an MSCA approved repository (Zenodo).
Exploitation and dissemination: Throughout the project, the researcher presented results and delivered reports, was involved in discussions with different project partners and participated in IP generation within the company. The researcher was actively engaged in public outreach (including Falling Walls finalist 2020 & jury member 2021, OTS Outreach Committee, Young Researcher Science Communication webinar presenter and AAAS Skills for Resilient Researchers webinar speaker) and engagement (as well as participation in scientific conferences and societies, including the OTS General Meeting 2020 & 2021, MSCA Cancer Research event and DNA nanotechnology webinar). A peer-reviewed publication was generated following on from this work, and is available with open-access via an MSCA approved repository (Zenodo).
This project's focus was the development of a preclinical candidate, as well as answering fundamental questions on nanoparticle delivery. We successfully engineered delivery constructs with alternative biodistribution patterns), and are currently developing a lead candidate. Methods developed during the course of this project have also helped us understand the mechanisms of action for drug delivery. This work opened new avenues for Sixfold, as well as for RNA delivery systems in general.
The data generated during this project is key short-term to understanding the interactions of Sixfold’s delivery technology in vivo, which is essential to developing the product, eventually leading to Phase I clinical trials. Longer-term, Sixfold’s RNA delivery systems could have a large impact on society, including more accessible and personalisable healthcare for otherwise “undruggable” diseases and less off-target effects for patients. Socio-economically, this will lead to reduced costs to develop/deliver RNA therapies, and skilled job creation for scientists with RNA and manufacturing expertise within Europe.
The data generated during this project is key short-term to understanding the interactions of Sixfold’s delivery technology in vivo, which is essential to developing the product, eventually leading to Phase I clinical trials. Longer-term, Sixfold’s RNA delivery systems could have a large impact on society, including more accessible and personalisable healthcare for otherwise “undruggable” diseases and less off-target effects for patients. Socio-economically, this will lead to reduced costs to develop/deliver RNA therapies, and skilled job creation for scientists with RNA and manufacturing expertise within Europe.