Abstract 3160: Silicon membrane technology enables novel live-cell assays for screening impermeable compounds prior to medchem optimization

Abstract Cell permeability poses a significant challenge to understanding target biology and exploring structure/function interactions of potential drug candidates. As a result, many experiments are performed in biochemical or lysate-based systems, which often fail to replicate the conditions of a live cell, leading to expensive and time-consuming downstream failures. Portal Biotechnologies has created an innovative intracellular delivery platform that leverages silicon membrane-based mechanoporation technology to directly deliver otherwise non-permeable cargos, such as small molecules, peptides, PROTACs, DELs, macrocycles, and probes, into the cytosol. Our research shows that mechanoporation causes minimal disruption to cellular function compared to other techniques like electroporation, which tend to impose stricter cargo limitations and inflict more cellular damage. This platform has also shown early success in delivering probe molecules for innovative intracellular assays, including LgBiT/HiBiT systems for protein degradation studies. Furthermore, we have demonstrated efficient co-delivery of diverse cargos like oligonucleotides, antibodies, and nucleic acids, achieving delivery rates exceeding 80% while maintaining cell viability above 80%.The platform has been validated across a variety of cell types, including widely used cancer cell lines and primary cells such as human immune cells and stem cells. The straightforward mechanical delivery approach enables scalability and seamless integration with liquid-handling systems for high-throughput applications. This capability allows for the automated screening of molecules previously unsuitable for live-cell assays, thereby enhancing the efficiency of drug discovery at multiple stages. By enabling live-cell assays, the Portal platform aims to offer novel biological insights, reduce target-related risks, and lower the likelihood of failures during lead optimization. Citation Format: Zhihui Song, Sophia Hirsch, Andrew Laroque, Jacquelyn Hanson, Alec Barclay, Armon Sharei, Darby Kreienberg, Eleni Rogers, Monique Richards, Crystal Tsui. Silicon membrane technology enables novel live-cell assays for screening impermeable compounds prior to medchem optimization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3160.