Nanoparticles Mimicking Platelets and Platelet Cloaking
Authors: Zhang Liangfang 
Published: November 2019

The diverse functions played by platelets such as immune evasion, subendothelium adhesion, and pathogen interactions hinge on unique surface moieties presented on the platelet membrane. This has inspired our recent development of platelet-mimicking nanoparticles by collecting and translocating human platelet membrane onto the surface of synthetic nanoparticles. The resulting platelet-like nanoparticles (denoted 'PNPs') possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. The PNPs faithfully present the entire surface antigens and their functions that are otherwise difficult to replicate using bottom-up approaches. First, we demonstrate the use of PNPs to leverage the natural interaction of platelet membrane markers with multiple components present during atherogenesis for multifactored biological targeting and detection of atherosclerosis. In an experimental rat model of coronary restenosis, we demonstrate that the PNPs can selectively deliver loaded drugs to the damaged vasculatures, resulting in enhanced therapeutic efficacy as compared to nanocarriers without platelet membrane coating. We also show that the PNPs can effectively target imaging payloads to sites of atherosclerosis. We find that the PNPs bind not only to regions with significant plaque formation but also to areas that are preatherosclerotic and prone to plaque formation. Beyond simply providing contrast, this strategy also provides information about the underlying biology of the targeted regions, which may eventually be used to give a more complete picture of disease development over time. By using MRI imaging as a proof-of-concept modality, the PNP platform may be adapted toward a variety of imaging modalities for improving the prevention and management of cardiovascular diseases. To further demonstrate PNP platform technology, we use PNPs as platelet decoys to remove pathological autoantibodies in immune thrombocytopenia purpura (ITP) that otherwise cause a reduction in platelet counts. We show that PNPs can specifically bind with anti-platelet autoantibodies, which are directly responsible for reducing platelet counts. Upon binding, the interaction between the PNPs and the antibodies is strong, effectively neutralizing biological activity in vivo. In an antibody-induced thrombocytopenia animal model, mice treated with PNPs after challenging with antibodies can retain their platelet counts. Further, in a bleeding time assay, mice treated with PNPs exhibit normal hemostasis via effective clot formation, and average values are nearly identical to unchallenged controls. However, untreated mice or those administered with control nanoparticles bleed excessively due to lowered platelets counts and impaired hemostasis capacity. The ability to specifically neutralize anti-platelet antibodies in ITP presents a new option in the current landscape of treatment for the disease. Overall, these results demonstrate that coating with the platelet membrane is an effective approach for functionalizing nanomaterials. This development is expected to generate a variety of attractive nanomedicines for wide biomedical applications.

Disclosures
Zhang: Cellics Therapeutics, Inc: Consultancy, Equity Ownership; Cello Therapeutics, Inc: Consultancy, Equity Ownership.