Presenting a Universal Cell Engineering Solution

Cells function as molecular machines, orchestrating biological processes. To modify them or study their function, researchers need a reliable way to introduce various materials into the cell. This has presented a longstanding challenge. Existing methods, including electroporation or viral transduction, carry limitations such as toxicity and scalability issues.

“Existing technologies are reasonably effective at delivering DNA or RNA into standard cell lines, such as HEK or HeLa cells. Nanoparticles, electroporation and viral transduction can generally achieve this without major issues,” Dr. Armon Sharei, founder and CEO of Portal Biotechnologies, told Technology Networks at this year’s Society for Laboratory Automation and Screening (SLAS) international meeting. “However, the challenge arises when working with more delicate cell types, particularly primary cells, such as immune cells derived from patient blood or stem cells.”

These cells are far more sensitive to existing delivery methods. “For instance, electroporation – while effective for cancer cell lines, which are relatively robust – can severely compromise T cells, leading to high cytotoxicity or functional impairment. This sensitivity limits the use of traditional approaches in many critical applications,” Sharei explained.

The second major challenge is cargo diversity: “Current methods are largely restricted to nucleic acid delivery, yet there is a growing need to introduce a wider range of biomolecules, including proteins, peptides and small molecules. This is particularly relevant in drug discovery, where promising compounds often fail due to unknown intracellular barriers.” Researchers struggle to determine whether a compound’s lack of efficacy is due to poor cellular uptake or an inherent biological limitation.

Portal Bio has developed a microfluidic technology – The Gateway™ System – that uses thin silicon membranes with nanoscale pores – essentially a high-precision filter – to tackle this challenge. When cells pass through the pores, which are approximately 70% of their size, they undergo deformation, momentarily opening their membranes and enabling the controlled delivery of diverse molecules.

The platform is based on Sharei’s PhD research, during which he made an unexpected discovery. “We found that when cells are essentially ‘squished’ at high speeds, their membranes temporarily disrupt, allowing external materials to enter,” Sharei said.

Portal’s technology has a broad range of applications, from drug screening and discovery to advanced cell engineering for research and therapeutic purposes. Despite being only 2 years old, the company has secured over 50 customers, including 9 major pharmaceutical companies.

“In the areas where we operate, our technology tends to perform better in terms of cell viability and efficiency. For example, if existing methods using electric fields achieve 70% delivery with 70% viability, we typically reach 80% for both, or slightly higher. While this is an improvement, it’s not necessarily groundbreaking,” Sharei said.

Where Portal’s technology really stands out, he emphasized is in user cases where existing methods struggle or fail entirely: “Take B cells, for instance – they are notoriously difficult to work with. We can achieve 70–80% delivery, whereas current techniques essentially result in zero because they destroy the cells. The same applies to certain cargos, like peptides, proteins, or small molecules, which existing methods cannot effectively deliver. In contrast, we can achieve 70–80% efficiency in these cases. So, while in some areas we offer incremental improvements, in others, we provide a significant breakthrough.”

Enhancing drug screening efficiency

Portal’s technology overcomes some of the core challenges in drug discovery and development by allowing researchers to distinguish between permeability issues – which are potentially addressable through chemical modifications – and fundamental biological constraints, which would indicate a compound is unlikely to succeed.

“We’ve seen particular success in drug discovery applications especially with heterobifunctional molecules like proteolysis targeting chimeras (PROTACs). These larger small molecule drugs – which are currently a major focus in the pharmaceutical industry – are often too large tobe permeable to a cell by default,” Sharei said.

This creates a bottleneck in drug screening; pharma companies may identify many promising candidates in a biochemical screen, only to later discover that most are cell impermeable. “Often companies will screen, fore example, 1 billion compounds, and they find 100 that look interesting. Most of these 100 compounds are going to be impermeable to a cell,” Sharei explained. “Now, you could spend a lot of time and money doing the chemistry work required to make permeable versions, only to later find out that this compound was never going to work biologically. Portal Bio helps these companies skip to the answer. They can deliver all 100 compounds, note the 10 that actually work biologically, and go on to invest time and money into the chemistry for those rather than the whole set.”

A related challenge exists with peptide and macrocycle drugs, which often suffer from the same permeability issues. Portal Bio’s approach lets researchers immediately determine whether a candidate is worth pursuing, reducing wasted effort on molecules that would never have been viable.

“Another key application in drug discovery relates to our collaboration with Promega, where we enable the intracellular delivery of previously impermeable probe agents. Promega develops reagents for detecting protein levels and other cellular biomarkers, but many of their probes traditionally only function in lysates or biochemical assays because they cannot cross cell membranes,” Sharei said.

“Our technology changes this by allowing these probes to enter live cells, providing real-time, dynamic insights into protein behavior. This has major implications for pharmacokinetics and pharmacodynamics, helping researchers fine-tune drug effects by observing protein interactions within a live-cell context rather than a disrupted lysate environment.”

At SLAS, the company launched its high-throughput system, Galaxy^TM, which is designed for seamless integration with automated platforms, alongside a clinical-scale version to support translational applications.

This launch, Sharei said, creates new opportunities to impact efficiencies, reduce waste and increase sustainability in drug discovery: “Our goal is to make the drug discovery process significantly more efficient, which should have positive downstream effects. By accelerating and streamlining drug development, we can help reduce both costs and environmental impact. A key benefit is minimizing the time and resources spent on expensive, environmentally hazardous chemistry for molecules that were never going to succeed.”

Looking beyond the technology’s current capabilities, Portal sees potential applications for Galaxy in emerging fields, such as synthetic biology.

“This is something we’re keen to explore with our initial users as we learn more about how they apply the technology,” Sharei said, though he expects the biggest enhancements to the company’s platform will come from stronger integrations with reagent providers.

“While the core delivery process is relatively straightforward and will likely see iterative improvements, the real game-changer will be the sophistication of the materials we deliver and how we analyze biological responses. The goal is to extract the richest information in the most practical and efficient way possible. Strengthening these partnerships will likely be the most impactful step forward,” Sharei concluded.