Protein nanoparticles are biomaterials composed entirely of proteins, with the protein sequence and structure determining the nanoparticle physicochemical properties. Upon exposure to physiological or environmental fluids, it is likely that protein nanoparticles, like synthetic nanoparticles, will adsorb proteins and this protein corona will be dependent on the surface properties of the protein nanoparticles. As there is little understanding of this phenomenon for engineered protein nanoparticles, the purpose of this work was to create protein nanoparticles with variable surface hydrophobicity and surface charge and establish the effect of these properties on the mass and composition of the adsorbed corona, using the fetal bovine serum as a model physiological solution. Albumin, cationic albumin, and ovalbumin cross-linked nanoparticles were developed for this investigation and their adsorbed protein coronas were isolated and characterized by gel electrophoresis and nanoliquid chromatography mass spectrometry. Distinct trends in corona mass and composition were identified for protein nanoparticles based on surface charge and surface hydrophobicity. Proteomic analyses revealed unique protein corona patterns and identified distinct proteins that are known to affect nanoparticle clearance in vivo. Further, the protein corona influenced nanoparticle internalization in vitro in a macrophage cell line. Altogether, these results demonstrate the strong effect protein identity and properties have on the corona formed on nanoparticles made from that protein. This work builds the foundation for future study of protein coronas on the wide array of protein nanoparticles used in nanomedicine and environmental applications.

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Bacterial enteric pathogens have evolved efficient mechanisms to suppress mammalian inflammatory and immunoregulatory pathways. By exploiting the evolutionary relationship between the gut and pathogenic bacteria, we have developed a potential mucosal therapeutic. Our findings suggest that engineered preparations of the Salmonella acetyltransferase, AvrA, suppress acute inflammatory responses such as those observed in inflammatory bowel disease (IBD). We created 125 nm diameter cross-linked protein nanoparticles directly from AvrA and carrier protein to deliver AvrA in the absence of Salmonella. AvrA nanoparticles are internalized in vitro and in vivo into barrier epithelial and lamina propria monocytic cells. AvrA nanoparticles inhibit inflammatory signaling and confer cytoprotection in vitro, and in murine colitis models, we observe decreased clinical and histological indices of inflammation. Thus, we have combined naturally evolved immunomodulatory proteins with modern bioengineering to produce AvrA nanoparticles, a potential treatment for IBD.

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Purpose.To compare the outcome of 145 women who underwent conventional total knee arthroplasty (TKA) with 77 women who underwent genderspecific TKA. Methods. Records of 222 women who underwent primary TKA using a conventional (n=145) or genderspecific (n=77) size E or F prosthesis for end-stage osteoarthritis were reviewed. The gender-specific prosthesis has a narrower mediolateral dimension. Patients were assessed for flexion, Oxford Knee Score, Knee Society function and knee scores, and Short Form-36 Health Survey preoperatively and postoperatively (at 6 months and 2 years). Results. The 2 groups were comparable in terms of age (67.8 vs. 68.1 years, p=0.789), body mass index (28.6 vs. 27.8 kg/m 2 , p=0.189), and preoperative scores. 12 women with conventional TKA and 4 women with gender-specific TKA were lost to followup. Compared with women with conventional TKA, women with gender-specific TKA had better flexion at 6 months (116° vs. 121.9°, p=0.007) and 2 years (118.7° vs. 124.6°, p=0.006), better bodily pain score at 2 years

Wnt pathway mutations can be found in nearly all colorectal cancers and a significant number of cancers of the liver, breast, prostate, endometrium and lung, among others. β-catenin is a key signaling hub in the Wnt pathway. Activated nuclear β-catenin forms a complex with TCF/LEF (T-cell factor/lymphoid enhancer binding factor) and drives the transcription of genes essential for cancer cell proliferation, survival, and metabolism. Blocking the β-catenin-TCF/LEF interaction offers an attractive therapeutic strategy to treat a large population of patients with WNT pathway mutations. However, β-catenin is considered as an “undruggable” target because it lacks tractable hydrophobic pockets for small-molecule binding. To address this challenge, we have successfully discovered and developed Helicon࣪ peptides targeting the β-catenin-TCF/LEF interaction. Using this novel modality, linear peptides are locked in a helical structure via a proprietary tethering technology to yield macrocyclic stapled peptides. Our helicons exhibit picomolar β-catenin binding affinity and nanomolar anti-proliferative cell-based activity. Cells treated with lead helicons followed by unbiased RNAseq GSEA indicate that the WNT/β-catenin pathways represent the top downregulated transcriptional signatures after treatment. Furthermore, PRISM cell line screening of more than 900 cell lines reveals that the most sensitive lines are enriched with APC and CTNNB1 mutations. Mechanistically, helicon treatment reduces nuclear β-catenin and alters the levels of cyclin D2/D3 and p27 in the sensitive lines. In vivo, our helicons display favorable pharmacokinetic properties, broad tissue distribution, and potent anti-tumor effects. Taken together, our data demonstrate β-catenin-targeting Helicon࣪ peptides have the potential to become the next-generation class of therapeutics to treat cancers with defined genetic mutations. Citation Format: Yaguang Si, Brian White, Sarah Cappucci, Jessica Ramirez, Charles Ponthier, Erica Visness, Kevin Ling, Peicheng Du, Minjung Choi, Ty Thomson, Josue Alfaro-Lopez, Pieter Beerepoot, Sorabh Agarwal, Paula Ortet, Miroslaw Lech, Zhi Li, Voké Olokpa, Ivan Jewett, Daniel La, Lihua Yu, John McGee, Martin Tremblay, Jonathan Hurov, Greg Verdine. Development of a novel and direct peptide Helicon࣪ inhibitor of β-catenin-TCF interaction with in vivo validation of transcriptional modulation and anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 345.

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