About

Huan Bao is an Associate Professor in the Department of Molecular Physiology and Biological Physics at the University of Virginia School of Medicine. His educational background includes a B.S. in Biological Science from Wuhan University, an M.S. in Biochemistry from the Chinese Academy of Sciences, and a Ph.D. in Biochemistry from the University of British Columbia. His research interests focus on the biophysics of membrane pore formation and the research and therapeutic applications of lipid nanoparticles. His work involves studying the fundamental mechanisms of membrane dynamics and applying this knowledge to develop novel biomedical technologies.

Research topics

• Biochemistry
• Biology
• Neuroscience
• Medicine
• Pathology
• Biophysics
• Materials science
• Chemistry
• Cell biology
• Nanotechnology

Selected publications

• Lipid bilayers determine allostery but not intrinsic affinity of cAMP to pacemaker channels

  Nature Communications · 2026-05-02

  articleOpen access

  The binding of cyclic adenosine monophosphate (cAMP) to hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels regulates cardiac pacemaking but key aspects of the mechanism of ligand-dependent regulation remain unresolved. Here, we examine the role of the lipid environment by reconstituting purified human HCN channels into lipid nanodiscs and measuring successive cAMP binding to single HCN channels using nanophotonic waveguides. Regardless of nanodisc size or lipid composition, cAMP molecules bind cooperatively to HCN channels in lipid bilayers, unlike channels solubilized in detergents. The affinity of the first ligand remains unchanged across conditions, indicating that the bilayer selectively alters higher-order ligation states. Cryo-EM structures of apo- and holo-HCN channels reveal additional lipid densities that are weak or absent in detergent-solubilized preparations. Together, these findings show that the lipid bilayer is both necessary and sufficient to induce cooperative ligand binding in HCN channels, thereby enhancing their sensitivity to gating stimuli.

  PublisherDOI

• BPS2025 - Designer nanodiscs to probe and reprogram membrane fusion and pore formation

  Biophysical Journal · 2025-02-01

  article1st authorCorresponding
  PublisherDOI

• DeFrND: detergent-free reconstitution into native nanodiscs with designer membrane scaffold peptides

  Nature Communications · 2025-08-26 · 8 citations

  articleOpen accessSenior author

  Membrane scaffold protein-based nanodiscs have facilitated unprecedented structural and biophysical analysis of membrane proteins in a near-native lipid environment. However, successful reconstitution of membrane proteins in nanodiscs requires prior solubilization and purification in detergents, which may impact their physiological structure and function. Furthermore, the detergent-mediated reconstitution of nanodiscs is unlikely to recapitulate the precise composition or asymmetry of native membranes. To circumvent this fundamental limitation of traditional nanodisc technology, we herein describe the development of membrane-solubilizing peptides to directly extract membrane proteins from native cell membranes into nanoscale discoids. By systematically protein engineering and screening, we create a class of chemically modified Apolipoprotein-A1 mimetic peptides to enable the formation of detergent-free nanodiscs with high efficiency. Nanodiscs generated with these engineered membrane scaffold peptides are suitable for obtaining high-resolution structures using single-particle cryo-EM with native lipids. To further highlight the versatility of our approach, we directly extract a sampling of membrane signaling proteins with their surrounding native membranes for biochemical and biophysical interrogations. To bypass the limitations of detergents, Ren et al. developed peptide scaffolds that extract membrane proteins directly into lipid nanodiscs, preserving the native environment for structural and functional studies of previously inaccessible membrane protein complexes

  PublisherOA PDFDOI

• Recent Advances in the Delivery of Bone Morphogenetic Proteins for Targeting Glioma: An Updated Review

  International Journal of Nanomedicine · 2025-05-01

  reviewOpen access1st authorCorresponding

  Bone Morphogenetic Proteins might be the most prospective in glioma treatment because of the facts that they can differentiate glioma cells, inhibit tumor growth and manage glioma stem cells. Its clinical application is hindered by several challenges, including limited permeability across the blood-brain barrier, which impedes effective delivery to the central nervous system; high susceptibility to enzymatic degradation, which compromises stability and therapeutic efficacy; and nonselective binding, which reduces specificity and may result in unintended off-target effects. This review systematically covers the advanced BMP delivery systems such as nanoparticles, smart carriers, gene therapy, and exosome-based system. Hydrogels, scaffolds, and microspheres' local delivery methods are also discussed as prospective options. The in vitro studies reveal that BMPs are effective and using in vivo glioma models there is also evidence of the effectiveness of BMPs. In addition, new clinical trials reveal concern with safety, tolerability, and therapeutic effects of BMPs, especially their combination with chemotherapy and immunotherapy. BMP specificity and therapeutic performance are further optimized by Personalized medicine and CRISPR/Cas engineering. However, regulatory barriers and product commercialization are challenging issues. This review highlights the need for novel approaches and advanced technologies to address the challenges associated with BMP delivery, aiming to establish BMP-based therapies as an effective treatment strategy for glioma.

  PublisherOA PDFDOI

• Universal Low-Frequency Noise Black-Box Attack on Visual Object Tracking

  Symmetry · 2025-03-19 · 1 citations

  articleOpen access

  Adversarial attacks on visual object tracking aim to degrade tracking accuracy by introducing imperceptible perturbations into video frames, exploiting vulnerabilities in neural networks. In real-world symmetrical double-blind engagements, both attackers and defenders operate with mutual unawareness of strategic parameters or initiation timing. Black-box attacks based on iterative optimization show excellent applicability in this scenario. However, existing state-of-the-art adversarial attacks based on iterative optimization suffer from high computational costs and limited effectiveness. To address these challenges, this paper proposes the Universal Low-frequency Noise black-box attack method (ULN), which generates perturbations through discrete cosine transform to disrupt structural features critical for tracking while mimicking compression artifacts. Extensive experimentation on four state-of-the-art trackers, including transformer-based models, demonstrates the method’s severe degradation effects. GRM’s expected average overlap drops by 97.77% on VOT2018, while SiamRPN++’s AUC and Precision on OTB100 decline by 76.55% and 78.9%, respectively. The attack achieves real-time performance with a computational cost reduction of over 50% compared to iterative methods, operating efficiently on embedded devices such as Raspberry Pi 4B. By maintaining a structural similarity index measure above 0.84, the perturbations blend seamlessly with common compression artifacts, evading traditional spatial filtering defenses. Cross-platform experiments validate its consistent threat across diverse hardware environments, with attack success rates exceeding 40% even under resource constraints. These results underscore the dual capability of ULN as both a stealthy and practical attack vector, and emphasize the urgent need for robust defenses in safety-critical applications such as autonomous driving and aerial surveillance. The efficiency of the method, when combined with its ability to exploit low-frequency vulnerabilities across architectures, establishes a new benchmark for adversarial robustness in visual tracking systems.

  PublisherOA PDFDOI

• Nanodiscs remain indispensable for Cryo-EM studies of membrane proteins

  Current Opinion in Structural Biology · 2025-04-08 · 10 citations

  review
  PublisherDOI

• DeFrND: detergent-free reconstitution into native nanodiscs with designer membrane scaffold peptides

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-08 · 3 citations

  preprintOpen accessSenior author

  Membrane scaffold proteins-based nanodiscs (NDs) have facilitated unprecedented structural and biophysical analysis of membrane proteins in a near-native lipid environment. However, successful reconstitution of membrane proteins in NDs requires prior solubilization and purification in detergents, which may impact their physiological structure and function. Furthermore, the detergent-mediated reconstitution of NDs is unlikely to recapitulate the precise composition or asymmetry of native membranes. To circumvent this fundamental limitation of traditional ND technology, we herein describe the development of membrane-solubilizing peptides to directly extract membrane proteins from native cell membranes into nanoscale discoids. By systematically protein engineering and screening, we created a new class of chemically modified Apolipoprotein-A1 mimetic peptides to enable the formation of detergent-free NDs (DeFrNDs) with high efficiency. NDs generated with these engineered membrane scaffold peptides are suitable for obtaining high-resolution structures using single-particle cryo-EM with native lipids. To further highlight the versatility of DeFrNDs, we directly extract a sampling of membrane signaling proteins with their surrounding native membranes for biochemical and biophysical interrogations.

  PublisherOA PDFDOI

• Exosomes-based immunotherapy for cancer: Effective components in the naïve and engineered forms

  International Immunopharmacology · 2024-07-21 · 3 citations

  review1st author
  PublisherDOI

• Targeting Recycling Endosomes to Potentiate mRNA Lipid Nanoparticles

  Nano Letters · 2024-04-19 · 22 citations

  articleOpen accessSenior authorCorresponding

  mRNA lipid nanoparticles (LNPs) have emerged as powerful modalities for gene therapies to control cancer and infectious and immune diseases. Despite the escalating interest in mRNA-LNPs over the past few decades, endosomal entrapment of delivered mRNAs vastly impedes therapeutic developments. In addition, the molecular mechanism of LNP-mediated mRNA delivery is poorly understood to guide further improvement through rational design. To tackle these challenges, we characterized LNP-mediated mRNA delivery using a library of small molecules targeting endosomal trafficking. We found that the expression of delivered mRNAs is greatly enhanced via inhibition of endocytic recycling in cells and in live mice. One of the most potent small molecules, endosidine 5 (ES5), interferes with recycling endosomes through Annexin A6, thereby promoting the release and expression of mRNA into the cytoplasm. Together, these findings suggest that targeting endosomal trafficking with small molecules is a viable strategy to potentiate the efficacy of mRNA-LNPs.

  PublisherOA PDFDOI

• Lipid bilayers determine allostery but not intrinsic affinity of cAMP binding to pacemaker channels

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-12-24 · 4 citations

  preprintOpen access

  Abstract Cyclic adenosine monophosphate (cAMP), a second messenger, binds to hyperpolarization and cyclic nucleotide-gated (HCN) ion channels and regulates the automaticity of pacemaking activity. While cellular studies suggest that cAMP binding to HCN channels exhibits unusual cooperativity, recent findings using purified detergent-solubilized channels indicate independent binding to each subunit. This discrepancy raises the question of whether the lipid environment or endogenous cellular cofactors influence cAMP-dependent gating. To address this, we reconstituted purified human HCN channels in nanodiscs and resolved cAMP binding energetics at single-molecule resolution using nanophotonic waveguides. Our measurements reveal that, in contrast to detergent-solubilized channels, cAMP binds cooperatively to HCN channels reconstituted in a variety of lipid nanodiscs. Remarkably, the presence of lipid bilayer promotes ligand-binding allostery but not intrinsic binding affinity. To explore the molecular basis of bilayer-induced allostery, we determine the cryo-EM structure of HCN1 in soy polar lipid nanodiscs at a nominal resolution of 3.77 Å resolution. Although the overall architecture is conserved, the average interfacial distance between the transmembrane domain and C-terminal domain of neighboring subunits are shorter in lipid nanodiscs. These findings indicate that the lipid bilayer regulates the function of pacemaker ion channels by enhancing inter-subunit interactions and underscore the fundamental role of membranes in amplifying the gating sensitivity of ion channels by promoting long-range cooperative interactions. Significance Statement Lipid membranes are essential for the structure and function of membrane proteins, including ion channels. Lipid mimetics, such as non-ionic detergents, are widely used as surrogates for the membrane environment in structural and biophysical studies. Here, we demonstrate that while the overall structure of the pacemaker ion channel remains similar, lipid membranes—unlike detergents—promote cooperative ligand-binding transitions by modifying interactions at intersubunit interfaces. These findings provide new insights into the mechanism of ion channel regulation by lipid membranes.

  PublisherOA PDFDOI

Frequent coauthors

• Edwin R. Chapman

  Howard Hughes Medical Institute

  46 shared

• Franck Duong

  University of British Columbia

  16 shared

• Jeehae Shin

  University of Virginia

  11 shared

• Loren L. Looger

  11 shared

• Jonathan S. Marvin

  Janelia Research Campus

  11 shared

• Shanwen Zhang

  10 shared

• Xiaochu Lou

  The University of Texas Southwestern Medical Center

  10 shared

• Amol V. Shivange

  California Institute of Technology

  9 shared

Education

• PhD, Biochemistry

  University of British Columbia

  2014

• MS

  Chinese Academy of Sciences

  2008

• BS, Biology Science

  Wuhan University

  2005