This award by the Biomaterials Program in the Division of Materials Research to the University of California, San Diego is to explore a highly innovative strategy for effective inhibition of harmful enzymes and to investigate the fundamental principles of this new approach. The proposal specifically targets phospholipase A2 (PLA2), key players in critical diseases including autoimmune diseases, cancers, and venomous injuries. Although PLA2 inhibition has been shown critical for the treatment of these diseases, safe and effective PLA2 inhibitors remain lacking. Herein, a nanostructure is constructed by using safe polymers and natural cell membranes. They are further functionalized to first 'lure' PLA2 for an attack and then 'kill' the incoming PLA2. The resulting nanoparticles (denoted "lure and kill" and abbreviated 'L&K-NP') combine PLA2 stimulation and inhibition, two seemingly counteracting functions, together for synergistic inhibition of the enzyme. Meanwhile, these nanoparticles preserve the functions of inhibitors and simulants while suppressing their toxicity otherwise unsafe for direct use. L&K-NPs also feature modular and tailorable design, representing a platform anti-PLA2 technology. The proposal will also carry out well-planned education components as an integral part of the project. The outcome is expected to contribute significantly to the continual growth of biomaterials science and engineering. Particular efforts will be dedicated to training a new generation of skilled and collaborative researchers and educators in the field of biomaterials and nanomedicine.

Technical Abstract

The research objective of this award is to develop and investigate a novel biomimetic nanoparticle platform with an integrated "lure and kill" mechanism for effective inhibition of phospholipase A2 (PLA2), a class of enzymes responsible for numerous diseases. Specifically, the design leverages nanoparticles coated with natural cell membranes that are susceptible to PLA2 attack. However, instead of being a simple sacrificial approach against PLA2, the proposed design incorporates two additional components: PLA2 stimulants such as melittin that spontaneously insert into the membrane and 'lure' the enzyme for an attack, and PLA2 inhibitors with a lipid-like structure that, upon membrane digestion, expose themselves to 'kill' PLA2. The resulting nanoparticles (denoted L&K-NPs) incorporate both PLA2 stimulants and inhibitors within the cell membrane, therefore eliminating the toxicity associated with free molecules of the stimulants and inhibitors for safe use. To achieve the primary goal, three specific research tasks will be pursued: (1) fabricate and optimize L&K-NP formulation, (2) validate L&K-NPs for preventing cell damage from venomous PLA2, and (3) extend L&K-NPs to inhibit mammalian PLA2 by using macrophage membrane coating. Furthermore, through this project, the PI will train a team of interdisciplinary and multi-level collaborative young investigators, provide minority students with stimulating research experience, and enhance scientific education among K-12 students and community at large.

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.

National Science Foundation (NSF)
Division of Materials Research (DMR)
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Randy Duran
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University of California San Diego
La Jolla
United States
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