Nanoparticles for Modulating mTOR Signaling in Platelets

Abstract

A recent Forum article in TiBTECH by Hulea et al. discussed the biomedical potential of mammalian target of rapamycin (mTOR)-modulating nanoparticles and their applications in human diseases [1]. They described the inhibition of mTOR activation by engineered nanoparticles and hypothesized their potential therapeutic applications in cancer and cardiovascular, inflammatory, neurological, and metabolic disorders [1]. Previous studies have demonstrated the central role of mTOR in platelet functions [2]. Combining those ideas, we propose here the potential of mTOR-modulating nanoparticles to regulate the key functions of human platelets, which are tiny anucleate myeloid blood cells, unique to mammals, that mediate hemostasis and thrombosis 3 and 4. The highly flexible and compatible physicochemical properties of nanoparticles are a good fit for platelet interactions 1 and 5. Therefore, mTOR-modulating nanoparticles in platelets might be useful in regulating platelet functions in hemostasis and thrombosis. Nanoparticles for Mediating Platelet Function by Modulating mTOR Signaling Although numerous studies have characterized mTOR signaling in most nucleated cells, its role in anucleate platelets remains unknown. However, recent advances in biotechnological techniques, including next-generation RNA sequencing and hybridization-based microarrays, have established mTOR as one of the most abundant proteins in human platelets, regulating 10–15% of the total translation of mRNA [3]. Transcriptome and mRNA splicing studies in platelets have revealed that anuclear platelets have remarkably specialized translational control pathways that are regulated in a signal-dependent manner, including, for example, the synthesis of fibrin-condensing Bcl-3 mediated by mTOR 2 and 3. Recombinant immunoprecipitation technology and real-time illuminated DIC optics have been used to demonstrate that mTOR and its downstream effector S6K1 mediate platelet activation and spreading, and the persistence of platelet aggregate stability 2 and 4. Therefore, mTOR is a potential therapeutic target in regulating platelet function. Recently, engineered nanoparticles have been studied as attractive disease-modifying agents 5 and 6. The better-characterized role of platelets as circulating sentinels for vascular and thrombotic disorders has paved the way for the design of various types of functional nanoparticle [5]. To overcome the limitations of synthetic antiplatelet drugs, nanoparticles mimicking either platelets or mechanisms of platelet adhesion and aggregation have shown promise in preclinical studies, although they were not so successful at the clinical level 5 and 6 (Table 1). Nanoparticles comprising liposomes and PEGylated and nonPEGylated cetyl alcholol/polysorbate have been shown to block agonist-induced platelet aggregation, but exhibited nonspecific interactions with other blood cells 5 and 6. Nevertheless, targeting mTOR with nanoparticles could be an effective alternative, given their successful applications in nuclear cells [1]. mTOR-modulating nanomedicine approaches can maintain platelet homeostasis (number and shape) and can only alter platelet functions, leveraging drug delivery concepts to hemostasis and thrombosis.