SBIR Phase II: High-throughput De-novo Peptide Sequencing with Metasurface Optics

The Broader/Commercial impact of this Small Business Innovation Research (SBIR) Phase II project is to understand and control the proteins that drive immune responses, in order to create improved immune-modulating medicines. Healthy and robust immune systems are able to identify diseased proteins and target them for elimination. However, as humans age or immune systems weaken, immune cells become less adept at recognizing diseased proteins. Cancer, neurodegeneration, and autoimmune disorders are driven in part by dysfunctional communication between immune cells and diseased cells. Yet, current knowledge about which proteins drive immune responses is extremely limited. The estimated number of possible proteins interacting between immune cells and diseased cells exceeds the number of stars in the visible universe, and current techniques to investigate these proteins can only see a small fraction. If these diseased proteins could be identified, they would provide the key insight needed to create improved medicines - spanning targeted cancer therapies, autoimmunity treatments, and even medicines that prevent neurodegeneration. Such insights could not only drive improved health-spans, but also reduce costs associated with ineffective treatments that do not properly target the diseased cells, and increase US competitiveness in biotechnology and artificial intelligence (AI) of biological systems. The proposed project will develop a technology for de-novo sequencing of the peptides that drive immune responses. All cells display surface peptide fragments that are the product of protein degradation; these ‘immunopeptides’ serve as beacons to the immune system about the health or disease state of a cell. Knowledge of the immunopeptide landscape for different diseases and across patient populations can enable the development of effective immune-modulating medicines that can guide one’s immune system to target diseased cells (such as in cancer or infectious diseases) or to dampen the reactivity towards the proteins that are driving autoimmune disorders. The proposed research will demonstrate direct-from-tissue sequencing of immunopeptides, utilizing label-free methods based on the peptide’s vibrational spectral signature. Aim 1 of this project will optimize and scale a silicon-based chip that enables single molecule immunopeptide detection across hundreds of millions of sensors and is manufacturable in a complementary metal-oxide-semiconductor (CMOS) foundry. Aim 2 will develop optical hardware that enables high throughput collection of over 10 million vibrational spectra per day. Aim 3 of the project will demonstrate de-novo sequencing across millions of immunopeptides. Upon completion, this Phase II project will provide the core technological innovations for a high-throughput, high-resolution peptide sequencing technology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.