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Advances in AAV capsid engineering: Integrating rational design, directed evolution and machine learning

molecular Therapy 2025年第5期33卷 1937-1945页

作者： Nisanov, Alan M. Rivera de Jesús, Julio A. Schaffer, David V. Department of Chemistry University of California Berkeley Berkeley 94720 CA United States Department of Chemical and Biomolecular Engineering University of California Berkeley Berkeley 94720 CA United States Department of Bioengineering University of California Berkeley Berkeley 94720 CA United States Graduate Program in Bioengineering University of California Berkeley San Francisco and University of California Berkeley 94720 CA United States Department of Neurological Surgery University of California San Francisco 94143 CA United States Department of Molecular and Cell Biology University of California Berkeley Berkeley 94720 CA United States

Adeno-associated virus (AAV) has emerged as a highly promising vector for human gene therapy due to its favorable safety profile, versatility, and ability to transduce a wide range of tissues. However, natural AAV serotypes have shortcomings, including suboptimal transduction efficiency, pre-existing immunity, and a lack of tissue specificity, that hinder their therapeutic potential. To address these challenges, significant efforts are being applied to engineer novel AAV capsids. Rational design leverages structural insights to enhance capsid properties, directed evolution enables unbiased selection of superior variants, and machine learning accelerates discovery by computational analysis of high-throughput screening results to enable predictive algorithms. These strategies have yielded novel capsids with improved transduction efficiency, reduced immunogenicity, and enhanced tissue targeting. Future advances that continue to integrate such multi-disciplinary approaches will further drive the clinical translation of AAV-based therapies. © 2025 The Authors

关键词： AAV directed evolution gene therapy high-throughput screening machine learning next generation sequencing NGS rational design

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Resolving Contradictory Estimates of Band Gaps of Bulk PdSe2: A Wannier-Localized Optimally-Tuned Screened Range-Separated Hybrid Density Functional Theory Study

arXiv

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arXiv 2025年

作者： Florio, Fred Camarasa-Gómez, María Ohad, Guy Naveh, Doron Kronik, Leeor Ramasubramaniam, Ashwin Department of Mechanical and Industrial Engineering University of Massachusetts Amherst AmherstMA01003 United States Department of Molecular Chemistry and Materials Science Weizmann Institute of Science Rehovoth7610001 Israel Institute for Nanotechnology and Advanced Materials Bar-Ilan University Ramat Gan52900 Israel Materials Science and Engineering Graduate Program University of Massachusetts Amherst AmherstMA01003 United States

Palladium diselenide (PdSe2)—a layered van der Waals material—is attracting significant attention for optoelectronics due to the wide tunability of its band gap from the infrared through the visible range as a function of the number of layers. However, there continues to be disagreement over the precise nature and value of the optical band gap of bulk PdSe2, owing to the rather small value of this gap that complicates experimental measurements and their interpretation. Here, we design and employ a Wannier-localized optimally-tuned screened range-separated hybrid (WOT-SRSH) functional to investigate the electronic bandstructures and optical absorption spectra of bulk and monolayer PdSe2. In particular, we account carefully for the finite exciton center-of-mass momentum within a time-dependent WOT-SRSH framework to calculate the indirect optical gap and absorption onset accurately. Our results agree well with the best available photoconductivity measurements, as well as with state-of-the-art many-body perturbation theory calculations, confirming that bulk PdSe2 has an optical gap in the mid-infrared (upper-bound of 0.44 eV). More generally, this work further bolsters the utility of the WOT-SRSH approach for predictive modeling of layered semiconductors. Copyright © 2025, The Authors. All rights reserved.

关键词： Layered semiconductors

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Generative and predictive neural networks for the design of functional RNA molecules

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Nature Communications 2025年第1期16卷 1-17页

作者： Riley, Aidan T. Robson, James M. Ulanova, Aiganysh Green, Alexander A. Department of Biomedical Engineering Boston University Boston MA United States Biological Design Center Boston University Boston MA United States College of Arts and Sciences Biochemistry and Molecular Biology Program Boston University Boston MA United States Faculty of Computing and Data Sciences Boston University Boston MA United States Molecular Biology Cell Biology & Biochemistry Program Graduate School of Arts and Sciences Boston University Boston MA United States

RNA is a remarkably versatile molecule that has been engineered for applications in therapeutics, diagnostics, and in vivo information-processing systems. However, the complex relationship between the sequence, structure, and function of RNA often necessitates extensive experimental screening of candidate sequences. Here we present a generalized, efficient neural network architecture that utilizes the sequence and structure of RNA molecules (SANDSTORM) to inform functional predictions across a diverse range of settings. We pair these predictive models with generative adversarial RNA design networks (GARDN), allowing the generative modelling of a diverse range of functional RNA molecules with targeted experimental attributes. This approach enables the design of novel sequence candidates that outperform those encountered during training or returned by classical thermodynamic algorithms, and can be deployed using as few as 384 example sequences. SANDSTORM and GARDN thus represent powerful new predictive and generative tools for the development of RNA molecules with improved function. © The Author(s) 2025.

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Cell-Instructive Biomaterials with Native-Like Biochemical Complexity

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Annual review of biomedical engineering 2025年第1期27卷 185-209页

作者： Marjan, Tuba Lafuente-Gómez, Nuria Rampal, Akaansha Mooney, David J. Peyton, Shelly R. Qazi, Taimoor H. Weldon School of Biomedical Engineering Purdue University West Lafayette Indiana USA email: tqazi@purdue.edu John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge Massachusetts USA email: mooneyd@seas.harvard.edu Wyss Institute for Biologically Inspired Engineering at Harvard University Boston MA United States Molecular and Cellular Biology Graduate Program University of Massachusetts Amherst MA United States John A. Paulson School of Engineering and Applied Sciences Harvard University Cambridge Massachusetts USA email: Department of Chemical Engineering University of Massachusetts Amherst MA United States Department of Biomedical Engineering Tufts University Medford Massachusetts USA email: Weldon School of Biomedical Engineering Purdue University West Lafayette Indiana USA email:

Biochemical signals in native tissue microenvironments instruct cell behavior during many biological processes ranging from developmental morphogenesis and tissue regeneration to tumor metastasis and disease progression. The detection and characterization of these signals using spatial and highly resolved quantitative methods have revealed their existence as matricellular proteins in the matrisome, some of which are bound to the extracellular matrix while others are freely diffusing. Including these biochemical signals in engineered biomaterials can impart enhanced functionality and native-like complexity, ultimately benefiting efforts to understand, model, and treat various diseases. In this review, we discuss advances in characterizing, mimicking, and harnessing biochemical signals in developing advanced engineered biomaterials. An overview of the diverse forms in which these biochemical signals exist and their effects on intracellular signal transduction is also provided. Finally, we highlight the application of biochemically complex biomaterials in the three broadly defined areas of tissue regeneration, immunoengineering, and organoid morphogenesis.

关键词： biomimetic scaffolds cell-adhesive ligands ECM extracellular matrix matricellular matrisome

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Magnetically separable silica-chitosan hybrids for efficient phosphate adsorption in aqueous solution

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Case Studies in Chemical and Environmental engineering 2025年 11卷

作者： Nuryono, Nuryono Sukamto, Sukamto Kunarti, Eko Sri Krisbiantoro, Philip Anggo Wan Abdullah, Wan Nazwanie Kamiya, Yuichi Department of Chemistry Faculty of Mathematics and Natural Sciences Universitas Gadjah Mada Bulaksumur Yogyakarta 55281 Indonesia of Life Science Hokkaido University Kita 10 Nishi 8 Kita-ku Sapporo 060-0810 Japan International Graduate Program of Molecular Science and Technology National Taiwan University No. 1 Sec. 4 Roosevelt Road Taipei 10617 Taiwan Molecular Science and Technology Program Taiwan International Graduate Program Academia Sinica Taipei 11529 Taiwan Department of Chemical Engineering College of Engineering National Taiwan University Taipei 10617 Taiwan School of Chemical Science Universiti Sains Malaysia Gelugor Penang 11800 Malaysia Faculty of Environmental Earth Science Hokkaido University Nishi 5 Kita 10 Kita-ku Sapporo 060-0810 Japan

In the present study, magnetic silica-chitosan hybrid (NMP@SiO2/CPTMS/Chi) was synthesized via a convenient and green sol-gel technique under room temperature, and the material was used as a highly efficient magnetic ... 详细信息

In the present study, magnetic silica-chitosan hybrid (NMP@SiO₂/CPTMS/Chi) was synthesized via a convenient and green sol-gel technique under room temperature, and the material was used as a highly efficient magnetic adsorbent for the removal of phosphate ions in water. While the magnetic properties of NMP from iron enable the material to be quickly separated via magnetic separation, the abundant active sites from the chitosan made the hybrid exhibit high adsorption capacity for phosphate ions. At pH 6, the removal of phosphate ions followed the pseudo-second-order (PSO) kinetic model with the adsorption rate constant (k₂) of 5.9 × 10^-3 mg g⁻¹ min⁻¹ and obeyed the Langmuir isotherm model with a maximum adsorption capacity (q_max) of 15.06 mg g⁻¹, outperforming most of the previously reported adsorbents. Stability tests and derivative thermogravimetry (DTG) analysis demonstrated that NMP@SiO₂/CPTMS/Chi remained stable even under strongly acidic conditions and possessed high thermal stability, respectively. The synergistic combination of high adsorption capacity, acid stability, thermal stability, and facile magnetic separation renders NMP@SiO₂/CPTMS/Chi a promising adsorbent for wastewater treatment and environmental remediation. Overall, this innovative material represents a significant advancement in phosphate removal, offering a sustainable and effective solution to address the global challenge of water pollution and protect aquatic ecosystems. © 2025 The Authors

关键词： Adsorption Chitosan Magnetic material Phosphate Silica Sol-gel

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BPS2025 - Disaggregation of biomolecular condensates by molecular chaperones is heterogeneous at the single-condensate level

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Biophysical Journal 2025年第3期124卷 415a-415a页

作者： Diangen Lin Kyle M. Lin David A. Drummond Allison H. Squires Harvard Graduate Program in Biophysics Harvard University Cambridge MA USA Graduate Program in Biophysical Sciences Medical Scientist Training Program University of Chicago Chicago IL USA Department of Biochemistry and Molecular Biology and Department of Medicine Section of Genetic Medicine University of Chicago Chicago IL USA Pritzker School of Molecular Engineering University of Chicago Chicago IL USA

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Combination of antimicrobial peptide and clinical antibiotic shows enhanced potency toward Acinetobacter baumannii infection

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European Journal of Pharmacology 2025年 999卷

作者： Yeh, Jih-Chao Yang, Chin-Hao Hazam, Prakash Kishore Selvaraj, Sanjay Prasad Lin, You-Ying Hsieh, Chu-Yi Liou, Je-Wen Chen, Jyh-Yih Marine Research Station Institute of Cellular and Organismic Biology Academia Sinica 23-10 Dawen Rd. Jiaushi Ilan 262 Taiwan Department of Biomedical Sciences and Engineering College of Medicine Tzu Chi University Hualien 970 Taiwan Molecular and Biological Agricultural Science Program Taiwan International Graduate Program Academia Sinica Taipei 11529 Taiwan Graduate Institute of Biotechnology National Chung Hsing University Taichung 402 Taiwan The IEGG and Animal Biotechnology Center and the Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung 402 Taiwan

The continued development of novel antimicrobial treatment strategies is crucial for maintaining an effective therapeutic arsenal, and antimicrobial peptides (AMPs) exhibit promising activities against a wide range of pathogens. In this study, we tested the combined effects of an AMP, TP4-3, and meropenem on Acinetobacter baumannii, which is responsible for many severe infections and is associated with high rates of overall mortality and morbidity. This study aimed to develop an effective combination therapy for microbial infections. TP4-3 and meropenem were found to act synergistically toward Acinetobacter baumannii and exhibit an activity profile better than those of the individual compounds. TP4-3 is an antimicrobial peptide with proven activity, low toxicity and extended stability. This AMP was combined with meropenem and tested for efficacy against A. baumannii using a panel of in vitro and in vivo tests. The combination of TP4-3 and meropenem exhibited robust activity against Acinetobacter baumannii pathogens. In particular, the combined treatment demonstrated significant antibiofilm properties and a lower degree of induced resistance than meropenem alone. Additionally, the combination showed an excellent activity profile in in vivo studies. Thus, the combination of TP4-3 and meropenem appears to be an effective strategy to mitigate the detrimental consequences of infections caused by this clinically relevant pathogen. Since the combination of TP4-3 and meropenem displayed better activity than the individual compounds, this strategy of combining AMPs with clinical antibiotics may be suitable for development of clinical treatments targeting various microbial infections. © 2025 Elsevier B.V.

关键词： Acinetobacter baumannii Antimicrobial peptide Gram-negative bacteria In vivo antimicrobial activity Stapled peptide Synergism

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Computational design of serine hydrolases

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Science (New York, N.Y.) 2025年第6744期388卷 eadu2454页

作者： Lauko, Anna Pellock, Samuel J. Sumida, Kiera H. Anishchenko, Ivan Juergens, David Ahern, Woody Jeung, Jihun Shida, Alexander F. Hunt, Andrew Kalvet, Indrek Norn, Christoffer Humphreys, Ian R. Jamieson, Cooper Krishna, Rohith Kipnis, Yakov Kang, Alex Brackenbrough, Evans Bera, Asim K. Sankaran, Banumathi Houk, K.N. Baker, David Department of Biochemistry University of Washington Seattle WA United States Institute for Protein Design University of Washington Seattle WA United States Graduate Program in Biological Physics Structure and Design University of Washington Seattle WA United States Department of Chemistry University of Washington Seattle WA United States Graduate Program in Molecular Engineering University of Washington Seattle WA United States Paul G. Allen School of Computer Science and Engineering University of Washington Seattle WA United States Medical Scientist Training Program University of Washington Seattle WA United States Howard Hughes Medical Institute University of Washington Seattle WA United States Department of Chemistry and Biochemistry University of California Los Angeles CA United States

The design of enzymes with complex active sites that mediate multistep reactions remains an outstanding challenge. With serine hydrolases as a model system, we combined the generative capabilities of RFdiffusion with an ensemble generation method for assessing active site preorganization at each step in the reaction to design enzymes starting from minimal active site descriptions. Experimental characterization revealed catalytic efficiencies (kcat/Km) up to 2.2 × 105 M-1 s-1 and crystal structures that closely match the design models (Cα root mean square deviations <1 angstrom). Selection for structural compatibility across the reaction coordinate enabled identification of new catalysts remove with five different folds distinct from those of natural serine hydrolases. Our de novo approach provides insight into the geometric basis of catalysis and a roadmap for designing enzymes that catalyze multistep transformations.

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Cdkn1a silencing restores myoblast differentiation by inducing selective apoptosis in senescent cells

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Cellular and molecular Biology Letters 2025年第1期30卷 1-21页

作者： Kim, Sujin Gu, Bonsang So, Chan-Young Mantik, Keren Esther Kristina Jung, Seung-Hyun Moon, Sohee Park, Dong-Ho Kwak, Hyo-Bum Cho, Jinkyung Cho, Eun-Jeong Lee, Jae-Seon Kang, Ju-Hee Department of Pharmacology Inha University College of Medicine 100 Inha-Ro Michuhol-Gu Incheon 22212 South Korea Research Center for Controlling Intercellular Communication Inha University College of Medicine Incheon 22212 South Korea Program in Biomedical Science and Engineering Inha University Incheon South Korea Department of Biochemistry College of Medicine The Catholic University of Korea Seoul South Korea Integrated Research Center for Genomic Polymorphism College of Medicine The Catholic University of Korea Seoul South Korea Department of Medical Sciences Graduate School of The Catholic University of Korea Seoul South Korea Department of Kinesiology Inha University Incheon South Korea College of Sport Science Sungkyunkwan University Suwon South Korea Department of Molecular Medicine Inha University College of Medicine 100 Inha-Ro Michuhol-Gu Incheon 22212 South Korea

Background: Sarcopenia, characterized by a progressive loss of skeletal muscle mass and function, is associated with the accumulation of senescent muscle stem cells, which impair muscle regeneration and contributes to the decline in muscle health. Cdkn1a, which encodes p21, is a well-known marker of cellular senescence. However, it remains unclear whether p21 inhibition eliminates senescent myoblasts and restores the differentiation capacity. Methods: We performed transcriptomic analysis to identify genes related to aging-induced sarcopenia using 21 month-old Sprague–Dawley rats. To investigate the specific role of Cdkn1a gene in muscle aging, we used an in vitro model of ceramide-induced senescence in myoblasts, which was verified by the upregulation of p21 and increased senescence-associated beta-galactosidase (SA-β-gal) staining. To inhibit p21, we treated myoblasts with small interfering RNA (siRNA) targeting Cdkn1a. Using fluorescence-activated cell sorting, we separated subpopulations of cells with high or low caspase 3/7 activity. Protein expression related to myogenesis, muscle atrophy, protein synthesis, and apoptosis were quantified by western blotting. Results: In our transcriptomic analysis, we identified Cdkn1a as an upregulated gene in both the soleus and white gastrocnemius muscles of aged rats, among 36 commonly upregulated genes. The upregulation of Cdkn1a appears to be linked to mitochondrial dysfunction and cellular senescence, underscoring its significance in sarcopenia pathogenesis. C2-ceramide treatment effectively induced senescence, as evidenced by increased p21 expression, enhanced SA-β-gal staining, decreased myogenesis, and increased apoptosis. Knockdown of p21 in ceramide-treated myoblasts significantly reduced SA-β-gal-positive cells, restored cell proliferation, reduced the expression of senescence-associated cytokines (i.e., interleukin (IL)-6 and tumor necrosis factor (TNF)-α), and selectively induced apoptosis in the senescent cell p

关键词： Cdkn1a Myogenesis p21 Sarcopenia Senescence Senolysis

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BPS2025 - Computational protein design for a novel porous DNA-protein co-crystal

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Biophysical Journal 2025年第3期124卷 321a-322a页

作者： Emma N. Magna Christopher D. Snow Cell and Molecular Biology Graduate Program Colorado State University Fort Collins CO USA Department of Chemical and Biological Engineering Colorado State University Fort Collins CO USA

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