Welcome to the Next Frontier in Drug Discovery: The Surfaceome
Contributed Commentary by Daniel Dlugolenski, Ph.D., Syncell
February 20, 2026 | The scientific community has made tremendous progress in the ability to identify and predict protein targets, advancing from bulk cellular analysis approaches to technologies with resolutions that now approach subcellular. Despite these achievements, fundamental questions in drug discovery remain difficult to answer: has the ideal protein target been identified, and is it easily accessible to intervention to accelerate the development pipeline and reduce candidate attrition?
Today, it’s estimated that 60% to 70% of all drugs on the market target cell-surface proteins, including monoclonal antibodies, antibody-drug conjugates, and CAR T-cell therapies. This is despite the fact that the underlying drug discovery work for those therapies was done without a tool designed to focus specifically on cell-surface proteins. Imagine how much more effective drug discovery programs could be with such a tool.
Drug discovery programs are carefully built around curated targets that are thought to be ideal, but unfortunately often fail in late-stage efficacy and safety evaluations. In order to reduce the on/off safety risks in these programs, one needs to know which proteins are present, where they are located, and which proteins they are associated with on the surface of the cell. These cell surface proteins, which collectively can be thought of as the “surfaceome,” serve as the primary communication and regulatory interface between a cell and its environment; they act as the actionable biology gateway for therapeutic intervention. It is more pressing than ever to know not only where a protein exists within the surfaceome, but what its disease-driving activities and therapeutic actionable states might be.
Conventional cellular analysis platforms struggle to deliver this information. Most of these tools can only search for known targets, making it impossible to discover unexpected or novel disease-associated proteins on the surface of a cell type of interest. To precisely define the molecular composition of the surfaceome, the field must enable truly unbiased proteomic discovery with nanoscale resolution.
Characterizing the Surfaceome
Characterizing the surfaceome is far more complicated than simply delivering sufficient resolution, whether through a single-cell analysis tool or a spatial proteomic platform. These proteins are notoriously difficult to study for a variety of reasons. Most proteins aren’t static on the cell membrane. They are transient, actively changing in response to cell state, environmental stimuli, and disease. Changes in abundance, localization, association, and function through trafficking, clustering, ligand engagement, and internalization contribute to the dynamic nature of the membrane and the difficulty in its interrogation. Any high-resolution tool will need to be able to capture this dynamic environment.
A major challenge in surfaceome-driven target discovery is the scarcity and complexity of membrane proteins. While plasma membrane proteins comprise about 2% of total protein abundance, they are highly important and actionable, as showcased by the number of FDA-approved drugs targeting cell membrane proteins. These proteins are hydrophobic, heterogeneous, and often low in abundance, making them difficult to isolate. Since the functional cell surface is only 10 nm to 50 nm, analysis tools must have exceptional spatial precision and sensitivity to accurately capture surface proteins without all the noise caused by contamination from intracellular proteins.
Key Drug Discovery Applications
In the near term, resolving the surfaceome will have the greatest impact for two key areas of the drug discovery process: target identification and biomarker discovery. In target identification, success is defined by both biological relevance and physical accessibility. Surfaceome analysis focuses on disease-associated proteins positioned at the cell membrane where therapeutic agents can directly engage their targets, maximizing the likelihood of efficacy. By prioritizing membrane-localized proteins, target discovery avoids the added uncertainty of intracellular delivery and enables earlier, clearer alignment between biological mechanism and therapeutic reach.
For biomarker discovery, surfaceome-associated proteins are ideal biomarkers because they are often biologically relevant, clinically accessible, and provide more than just measures of disease. They can define critical intervention points, resulting in translational actionability. Many of the biomarkers used today to match patients to precision therapies, such as EGFR in cancer, are cell-surface proteins.
In both cases, correctly characterizing the surfaceome allows drug discovery scientists to begin their search for a new drug or biomarker with a list of high-confidence hits. At a time when there are so many costly failures in phase 1 and 2 studies, it would be a much-needed change for biopharma companies to add new layers of actionable information earlier in the process to prioritize development of high-value targets, reduce validation efforts downstream, and minimize later-stage failures.
What’s Next
There are many widely used protein analysis tools available today, from spatial proteomic platforms based on immunofluorescence to laser capture microdissection to proximity labeling, but none of these traditional tools delivers the combination of nanoscopic resolution with unbiased discovery necessary to fully characterize the surfaceome.
By focusing on the goals of resolution, discovery, and the ability to unravel complex systems, we can move toward the next frontier of drug discovery with greater confidence that new targets and biomarkers will be successful. This will be a critical step forward in the era of precision medicine.
Daniel Dlugolenski, Ph.D., serves as head of product management at Syncell, where he works to deliver high-resolution protein analysis tools for novel applications such as resolving the surfaceome. He can be reached at daniel.dlugolenski@syncell.com.