Engineering nanomaterials are increasingly considered promising and powerful biomedical tools or devices for imaging, drug delivery, and cancer therapies, but few nanomaterials have been tested in clinical trials. This wide gap between bench discoveries and clinical application is mainly due to the limited understanding of the biological identity of nanomaterials. When they are exposed to the human body, nanoparticles inevitably interact with bodily fluids and thereby adsorb hundreds of biomolecules. A “biomolecular corona” forms on the surface of nanomaterials and confers a new biological identity for NPs, which determines the following biological events: cellular uptake, immune response, biodistribution, clearance, and toxicity. A deep and thorough understanding of the biological effects triggered by the protein corona in vivo will speed up their translation to the clinic. To date, nearly all studies have attempted to characterize the components of protein coronas depending on different physiochemical properties of NPs. Herein, recent advances are reviewed in order to better understand the impact of the biological effects of the nanoparticle–corona on nanomedicine applications. The recent development of the impact of protein corona formation on the pharmacokinetics of nanomedicines is also highlighted. Finally, the challenges and opportunities of nanomedicine toward future clinical applications are discussed.

Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

Purpose This phase I study assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Patients and Methods Pyrotinib was administered continuously, orally, once per day to patients who did not have prior exposure to tyrosine kinase inhibitors of HER2. Planned dose escalation was 80, 160, 240, 320, 400, and 480 mg. For pharmacokinetic analysis, timed blood samples were collected on day 1 and day 28. Next-generation sequencing was performed on circulating tumor DNA and genomic DNA from tumor samples. Results Thirty-eight patients were enrolled. The dose-limiting toxicity was grade 3 diarrhea, which occurred in two patients administered 480 mg of pyrotinib; thus, the maximum tolerated dose was 400 mg. Common pyrotinib-related adverse events included diarrhea (44.7% [17 of 38]), nausea (13.2% [five of 38]), oral ulceration (13.2% [five of 38]), asthenia (10.5% [four of 38]), and leukopenia (10.5% [four of 38]). The only grade 3 adverse event was diarrhea. Pharmacokinetic analyses indicated that pyrotinib exposure was dose dependent. The overall response rate was 50.0% (18 of 36), and the clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) was 61.1% (22 of 36). The median progression-free survival was 35.4 weeks (95% CI, 23.3 to 40.0 weeks). The overall response rate was 83.3% (10 of 12) in trastuzumab-naive patients and 33.3% (eight of 24) in trastuzumab-pretreated patients. Preliminary results suggest that PIK3CA and TP53 mutations in circulating tumor DNA ( P = .013) rather than in archival tumor tissues ( P = .474) may predict the efficacy of pyrotinib. Conclusion Continuous once-per-day pyrotinib was well tolerated and demonstrated promising antitumor activity in HER2-positive patients with metastatic breast cancer. The maximum tolerated dose was established as 400 mg. Diarrhea was the dose-limiting toxicity. The promising antitumor activity and acceptable tolerability of pyrotinib warrant its further evaluation in a phase II study.

CONSPECTUS: Engineered nanomaterials (ENMs) have been developed for imaging, drug delivery, diagnosis, and clinical therapeutic purposes because of their outstanding physicochemical characteristics. However, the function and ultimate efficiency of nanomedicines remain unsatisfactory for clinical application, mainly because of our insufficient understanding of nanomaterial/nanomedicine−biology (nano−bio) interactions. The nonequilibrated, complex, and heterogeneous nature of the biological milieu inevitably influences the dynamic bioidentity of nanoformulations at each site (i.e., the interfaces at different biological fluids (biofluids), environments, or biological structures) of nano−bio interactions. The continuous interplay between a nanomedicine and the biological molecules and structures in the biological environments can, for example, affect cellular uptake or completely alter the designed function of the nanomedicine. Accordingly, the weak and strong driving forces at the nano−bio interface may elicit structural reconformation, decrease bioactivity, and induce dysfunction of the nanomaterial and/or redox reactions with biological molecules, all of which may elicit unintended and unexpected biological outcomes. In contrast, these driving forces also can be manipulated to mitigate the toxicity of ENMs or improve the targeting abilities of ENMs. Therefore, a comprehensive understanding of the underlying mechanisms of nano−bio interactions is paramount for the intelligent design of safe and effective nanomedicines. In this Account, we summarize our recent progress in probing the nano−bio interaction of nanomedicines, focusing on the driving force and redox reaction at the nano−bio interface, which have been recognized as the main factors that regulate the functions and toxicities of nanomedicines. First, we provide insight into the driving force that shapes the boundary of different nano−bio interfaces (including proteins, cell membranes, and biofluids), for instance, hydrophobic, electrostatic, hydrogen bond, molecular recognition, metal-coordinate, and stereoselective interactions that influence the different nano−bio interactions at each contact site in the biological environment. The physicochemical properties of both the nanoparticle and the biomolecule are varied, causing structure recombination, dysfunction, and bioactivity loss of proteins; correspondingly, the surface properties, biological functions, intracellular uptake pathways, and fate of ENMs are also influenced. Second, with the help of these driving forces, four kinds of redox interactions with reactive oxygen species (ROS), antioxidant, sorbate, and the prosthetic group of oxidoreductases are utilized to regulate the intracellular redox equilibrium and construct synergetic nanomedicines for combating bacteria and cancers. Three kinds of electron-transfer mechanisms are involved in designing nanomedicines, including direct electron injection, sorbate-mediated, and irradiation-induced processes. Finally, we discuss the factors that influence th...

In this preclinical model, TRPC6 channels were essential for glioma development via regulation of G2/M phase transition. This study suggests that TRPC6 might be a new target for therapeutic intervention of human glioma.