About

Hai-Quan Mao is a professor of materials science and engineering and the director of the Institute for NanoBioTechnology at Johns Hopkins University. He is known for his work engineering novel nanomaterials for regenerative medicine and therapy delivery applications. Mao holds a joint appointment in the Translational Tissue Engineering Center and the Department of Biomedical Engineering at the School of Medicine. His research in regenerative engineering includes developing nanofiber scaffolds from synthetic and natural biomaterials for liver tissue engineering, stem cell expansion and differentiation, and soft tissue regeneration. He has discovered a synergistic effect between nanofiber topography and biochemical cues on the proliferation of human hematopoietic stem and progenitor cells, invented a more efficient HSC expansion method enabling various HSC-based cellular therapies, and engineered methods for promoting lineage-specific differentiation of neural (crest) stem cells. Additionally, Mao has developed tailored, nanofiber-based scaffolds for vascular engineering, skeletal muscle regeneration, spinal cord repair, and peripheral nerve regeneration. In therapeutic engineering, his contributions include understanding nanoparticle assembly mechanisms from polyelectrolyte complexes with plasmid DNA, RNA, or protein therapeutics, engineering DNA nanoparticles with tunable shapes that mimic natural viral particles, and developing scalable production methods for these therapeutic nanoparticles for local and systemic delivery of macromolecular therapeutics and vaccines. Mao has been elected a Fellow of the National Academy of Inventors, the American Institute for Medical and Biological Engineering, and the Royal Society of Chemistry. He holds 35 issued U.S. patents, six international patents, and over 60 provisional U.S. patent applications. He is also a co-founder of LifeSprout Inc. and SpaceTime Therapeutics, LLC. Mao has received numerous awards including the Young Investigator Award at the National University of Singapore, the NSF Faculty CAREER Award, Johns Hopkins University’s Cohen Translational Engineering Award, the Louis B. Thalheimer Award for Translational Research, and the Johns Hopkins Discovery Award. He serves as an associate editor of the journal Biomaterials and is on the editorial boards of ACS Biomaterials Science & Engineering and the Journal of Materials Chemistry B. Mao earned his BS in chemistry and PhD in polymer chemistry from Wuhan University in China and completed postdoctoral training at Johns Hopkins University School of Medicine. His professional memberships include several prominent societies in biomaterials, gene and cell therapy, and regenerative medicine.

Research topics

• Computer Science
• Cell biology
• Chemistry
• Biology
• Biochemistry
• Optics
• Materials science
• Biophysics
• Computational biology
• Physics
• History
• Genetics
• Molecular biology
• Nanotechnology

Selected publications

• Myoblast Therapy Ameliorates Skeletal Muscle Atrophy Resulting From Chronic Denervation

  Muscle & Nerve · 2026-04-25

  article

  INTRODUCTION/AIMS: Skeletal muscle undergoes progressive denervation-induced muscle atrophy (DIMA) after peripheral nerve injury that severely impairs the potential for motor functional recovery with reinnervation. There are currently no therapeutic strategies to reverse the deleterious effects of chronic DIMA, leaving affected patients with lifelong disability. Herein, we used a translational rodent forelimb nerve injury model to investigate whether targeted injection of syngeneic myoblasts to chronically atrophic muscle can reverse the histologic and functional consequences of DIMA. METHODS: Male Lewis rats underwent median nerve transection followed by immediate (positive control) or delayed repair. Following a plateau of motor function, myoblasts were injected into the digital flexor muscles (n = 5-6 per group), delivered in either saline or a nanofiber hydrogel composite (NHC) loaded with agrin- and insulin-like growth factor 1 (IGF-1)-releasing nanoparticles (npNHC). Serial functional assessments of stimulated grip strength and terminal histological evaluation were used to measure recovery. RESULTS: ) myoblast therapy caused sustained improvement in stimulated grip strength from pretreatment baseline (p < 0.05). Histological evaluation demonstrated that myoblast therapy, when delivered in npNHC, reversed whole muscle atrophy compared to positive controls [p = 0.997 and 0.996] and restored mean myofiber cross-sectional area [p = 0.244]. Correlation analysis demonstrated functional improvements were associated with increased myofiber cross-sectional area [r = 0.900, p = 3.01E-09]. DISCUSSION: This data indicates that targeted injection of syngeneic myoblasts can reverse the functional and histologic effects of DIMA in skeletal muscles and is a promising strategy for improving recovery after peripheral nerve injuries.

  PublisherDOI

• Engineering age-adaptive mRNA lipid nanoparticle cancer vaccines via reprogramming systemic gene expression

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-12

  articleOpen accessSenior authorCorresponding

  Lipid nanoparticle (LNP)-based mRNA vaccines have transformed cancer immunotherapy, yet their efficacy in older individuals, who represent the majority of cancer patients, remains poorly understood. Here, we uncover a critical and previously underappreciated barrier to mRNA LNP cancer vaccine performance in aged hosts: impaired systemic transgene expression. Using the SM-102 mRNA LNPs as a benchmark formulation, we show that while local immune activation and antigen presentation at the injection site and draining lymph nodes remain largely intact with age, transgene expression in peripheral organs, including the liver, lungs, and spleen, is markedly reduced. This deficit limits the magnitude and durability of CD8⁺ and CD4⁺ T cell responses and substantially compromises tumour control. Transcriptomic profiling further reveals that attenuated transgene expression parallels broad attenuation of antigen processing, presentation, and activation pathways in immune cells from aged animals, implicating impaired systemic mRNA translation as a central driver of the downstream immune defects and antitumour efficacy loss. Building on these insights, we identify a rationally selected LNP formulation that reestablishes distal antigen expression across age groups as an engineering strategy to revive T cell immunity, achieving full rescue of therapeutic efficacy in aged mice without additional intervention. Together, these findings establish systemic mRNA translation as a tuneable lever of vaccine performance and highlight that optimizing LNP formulations to sustain systemic transgene expression across age groups may enable next-generation, age-adaptive mRNA vaccines for cancer and other diseases of aging.

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• Fibroblast signaling influences macrophage-dependent, biomaterial-induced tissue remodeling

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-28

  articleOpen access

  Abstract The ability to induce tissue regeneration on demand using biomaterials remains a major goal in biomedical research, yet significant challenges persist. Among the most advanced biomaterial models, the nanofiber-hydrogel composite has demonstrated a striking ability to induce soft adipose tissue remodeling at the injection site without incorporating exogenous biological cues. 1,2 However, the underlying mechanisms that drive such a tissue response remain unclear. Here, we show that biomaterial-induced tissue remodeling is driven by sustained and controlled inflammation mediated by macrophages in strong communication with fibroblasts. Notably, both pro-inflammatory and anti-inflammatory signals remained elevated during this process in the long-term, challenging the prevailing notion that inflammation opposes remodeling. Using macrophage depletion in mice, we demonstrate that macrophages are essential for this process. Single-cell RNA sequencing further revealed robust fibroblast-to-macrophage signaling, contrasting with the conventional macrophage-to-fibroblast paradigm, and identified unique Spp1 ⁺ macrophages and Ctla2a ⁺ fibroblasts within the remodeling niche. These findings provide a comprehensive view of the immune landscape in biomaterial-induced tissue remodeling, highlighting key cellular interactions, prolonged kinetics, and unexpected signaling pathways. By defining key targets and fundamental principles, this work has broad implications for advancing biomaterial-induced tissue regeneration.

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• Buffer Valency Engineering Enables High-concentration and Shelf-stable DNA Transfection Particles for Viral Vector Production

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-05

  preprintOpen accessSenior authorCorresponding

  Cost-effective and scalable production is critical for advancing the clinical translation of adeno-associated virus (AAV)-mediated gene therapy. The widely used transient transfection method using plasmid DNA (pDNA)-loaded transfection particles for AAV production faces technical challenges due to instability of the particles and the concentration limits for particle preparation, hindering reproducibility and scalability. Here, we report a streamlined and scalable strategy to generate shelf-stable, highly concentrated pDNA/poly(ethylenimine) (PEI) transfection particles. By incorporating trivalent citrate ions in the dilution buffers, we kinetically modulate electrostatic complexation to achieve uniform nanoparticle assembly and prevent aggregation at high concentrations. This enables a tenfold increase in pDNA concentration in stabilized transfection particles from a typical range of 10-20 μg/mL to 200 μg/mL, while reducing the required dosing volume from 5-10% to 0.5% of the cell culture medium. The particle assembly process is robust to changes in mixing scale and timing and is compatible with standard workflows. We demonstrate equivalent AAV production efficiencies to standard methods and consistent performance in various production scales, which confirms the practical utility of this assembly method in developing robust, scalable, and cost-effective AAV manufacturing processes.

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• Abstract 848: Preclinical development of the lipid nanoparticle-based mRNA vaccine with multiple natural T cell epitopes for pancreatic cancer

  Cancer Research · 2025-04-21

  article

  Abstract Background: Immunotherapy has recently emerged as a promising avenue in cancer treatment; however, its effectiveness on pancreatic ductal adenocarcinoma (PDAC) is hindered by the lack of effector T cells in the tumor microenvironment. One of the strategies to overcome the resistance of PDAC to immunotherapy involves identifying immunogenic tumor-associated and specific antigens for the development of personalized cancer vaccines. The mRNA platform has become an attractive platform for antigen presentation. The delivery of mRNA cancer vaccines via lipid nanoparticles (LNPs) enables intracellular delivery and controlled release of the payload, offering improved vaccine efficacy. However, mRNA vaccines presenting human T cell epitopes often lack a preclinical model for antitumor immune efficacy testing. Methods: A syngeneic mouse model of PDACs was established by implanting KPC tumor cells into the livers by hemispleen surgery. mRNA vaccines expressing five 25-mer peptide regions were synthesized. Two mouse CD8+ T cell epitopes were predicted. Their MHC binding was tested by the T2 binding assay. CD8+ T cells specific for these two epitopes were examined by ELISpot assays and were quantified by ImmunoSpot ELISpot Reader to identify changes in IFN- secretion. Results: Using mass spectrometry analysis, we successfully identified natural HLA class I and class II-binding epitopes in the neoplastic tissues of human PDACs. For the design of mRNA vaccine, we chose five 25-mer peptide regions that each contains both class I and class II epitopes punctuated by AAY and GPGPG linkers and followed by an MITD sequence, which all aim to improve the efficiency of antigen presentation to dendritic cells. Using NetMHC, we predicted H2Kb or H2Db-binding epitopes LYPFPLAL and SMVQMTFL, within these five human peptide regions. The T2 binding assay showed a lack of evident binding of both peptides to the T2-Kb or T2-Db cells. However, The ELISpot assay showed that LYPFPLAL, but not SMVQMTFL, can induce the IFN- expression from CD8+ T cells derived from splenocytes of the KPC tumor mice vaccinated by a peptide vaccine containing both peptides. Therefore, this result confirmed that LYPFPLAL is a mouse CD8+ T cell epitope and can be used to monitor antigen-specific CD8+ T cell response in response to the mRNA vaccine treatment in the syngeneic mouse model of PDACs. Conclusions: Antitumor efficacy of our above-designed mRNA vaccine can be tested in the syngeneic mouse hemispleen model of KPC tumors. Mouse LYPFPLAL epitope-specific CD8+ T cell response can serve as a surrogate marker for the antitumor efficacy of this mRNA vaccine in mouse models for PDAC. Citation Format: Josephine Chang, Kevin Zheng, Yiming Li, Wanting Shan, Lei Zheng, Hai-Quan Mao, Juan Fu, Jiawei Zhou. Preclinical development of the lipid nanoparticle-based mRNA vaccine with multiple natural T cell epitopes for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 848

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• Abstract 3462: Novel delivery platform for temporally-controlled release of immunocytokines and immune checkpoint inhibitors to enhance cancer therapy

  Cancer Research · 2025-04-21

  article

  Abstract Interleukin-2 (IL-2) is a multifunctional cytokine that plays a critical role in the differentiation, proliferation, activation, and survival of immune cells and has been used therapeutically for over 30 years as a cancer treatment. Unfortunately, the cytokine’s narrow therapeutic window and its short circulation half-life have severely limited its clinical application. Strategies designed to bias the activities of IL-2 represent emergent and promising avenues in the treatment of cancer, as they afford the opportunity to selectively target and stimulate certain immune cell subtypes. Recently, our lab has developed one such therapy, termed an immunocytokine (IC), which fuses IL-2 to an anti-IL-2 antibody that biases the cytokine towards immunostimulatory activities while also extending its persistence in the bloodstream. Additionally, we further established that the IC was able to synergize with immune checkpoint inhibitors (ICIs) to effectively clear tumors through expansion of CD8+ T cells and stimulation of their effector functions. Interestingly, it was observed that the therapeutic effects of this combination treatment were highly sensitive to dosing regimen; specifically, robust antitumor activity was observed when IC was delivered after ICI, but not when the order was reversed. Building on this observation of time-dependent anti-cancer activity, here we expand upon this work through the development of a biomaterial system that will enable further exploration of the kinetics surrounding the combinatorial delivery landscape using IC and ICIs. Our biomaterial system involves formulation of nanoparticles that encapsulate IC and ICIs using a flash nano complexation and flash nanoprecipitation system. These particles are further enclosed within a hydrogel system for protection and sustained release within the tumor environment, controlling both the temporal and spatial distribution of the encapsulated immunotherapies. We have successfully designed and characterized the delivery platform and established time-dependent release of the therapeutic cargo. In vivo immune stimulation and tumor clearance studies are ongoing to further evaluate our approach. Overall, our work introduces an innovative and highly versatile bioengineering approach that can be tuned to optimize immunotherapy strategies in a wide range of cancer types. Citation Format: Pilar O'Neal, Julia Lu, Yicheng Zhang, Marek Kovar, Hai-Quan Mao, Jamie Spangler. Novel delivery platform for temporally-controlled release of immunocytokines and immune checkpoint inhibitors to enhance cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3462.

  PublisherDOI

• Buffer Valency Engineering Enables High-concentration and Shelf-stable DNA Transfection Particles for Viral Vector Production

  Research Square · 2025-10-23

  preprintOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Sequential flash nanocomplexation and flash nanoprecipitation enables scalable assembly of doxorubicin-loaded nanoparticles

  Nanomedicine Nanotechnology Biology and Medicine · 2025-07-15 · 2 citations

  articleSenior authorCorresponding
  PublisherDOI

• Engineering the immune and fibrotic response in VML

  The Journal of Physiology · 2025-05-05 · 4 citations

  reviewOpen access

  Volumetric muscle loss (VML) provides a significant challenge for regeneration, despite current treatments with free functional muscle transfer. VML injury overwhelms the native process of wound healing, leading to a dysregulated immune response and eventually fibrosis. Tissue engineered muscle grafts are a promising method of treatment without donor site morbidity. Tissue engineered muscle grafts not only provide structural support, but also address the myogenic deficit by transplanting satellite cells and myoblasts to supplement those lost as a result of injury and secrete additional stimuli to create a more pro-regenerative microenvironment. However, adequate treatment of VML also requires immune modulation and limiting fibrotic deposition. To address this, some approaches have targeted other cells involved in the injury response such as macrophages, regulatory T cells, fibroadipogenic progenitor, and myofibroblasts. Treatments that supplement myogenic cells at the same time as co-delivering either immune or fibrotic modulatory signals have demonstrated increased success. One limitation is that many of these treatments are being tested in models that exhibit limited fibrosis, and the observed benefits of treatment may not be seen in more clinically relevant scenarios. Future studies may also address the incomplete understanding of the cellular signalling responses that ameliorate fibrosis. We provide a summation of recent strategies employed for this purpose, as well as predictions about new strategies yet to be utilized in VML.

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• Lipid Nanoparticle-mediated Nucleic Acid Delivery for Microvascular Endothelial Cell Metabolic Modulation

  Physiology · 2025-05-01

  article

  RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive disease marked by increased pulmonary vascular resistance, leading to right ventricular failure and death. In PAH, microvascular endothelial cells (MVECs) abnormally proliferate to form plexiform lesions, which occlude the microvasculature. MVECs in PAH display oncogenic-like behaviors such as increased intracellular calcium and endothelial-mesenchymal transition (EndMT). These maladaptive MVEC phenotypic changes are thought to be driven, in part, by pathogenic metabolic shifts. Increased fatty acid oxidation (FAO) and ketogenesis (i.e. production of the ketone body beta-hydroxybutyrate; BOHB) were recently observed in PAH MVECs 1, 2 . Furthermore, inhibiting BOHB production attenuated MVEC proliferation. These data suggest that BOHB production may represent a druggable target in PAH. We have demonstrated that increased activity of Bdh1, a key enzyme in ketone metabolism, accompanies BOHB production in MVECs derived from an experimental rodent PAH model. As nanoparticle-mediated strategies can enable the direct modulation of specific metabolites without globally disrupting metabolic pathways, we sought to develop a lipid nanoparticle (LNP) optimized for MVECs. Since MVECs implicated in PAH undergo dynamic acquisition and loss of cell surface markers through EndMT, we pursued a compositional-based screening approach, as opposed to an active-ligand based targeting strategy, to assess transfection efficiency. We have designed an LNP for cell preferential uptake in MVECs to modulate levels of metabolites differentially implicated in PAH. We hypothesize LNP-mediated Bdh1 downregulation can rescue endothelial cell function in PAH. Methods: We pursued a multi-step screening approach to identify optimized formulations for modulating cellular metabolism using reporter nucleic acid cargo. Employing an established library of 649 formulations with SM-102 as the ionizable lipid, helper lipids of cationic (DDAB, DOTAP), zwitterionic (DSPC, DOPE), and anionic charge (18BMP, 18PG), cholesterol and DMG-PEG-2000, we evaluated the transfection efficiency of Luciferase mRNA-LNPs in Human Umbilical Vein Endothelial Cells 3, 4 . We then stratified top formulations by cationic helper lipid charge to enhance lung tropism and evaluated reporter plasmid-DNA transfection (24 h) and siRNA transfection (48 h) in control rat lung MVECs isolated as described previously 1 .Transfection efficiency was assessed with a luminescence microplate reader, flow cytometry, and fluorescent microscopy. Bdh1 was depleted in MVECs with small interfering RNA (siBdh1), using non-targeting siRNA as control, and assessed with RT-qPCR. Results: Two plasmid-DNA DOTAP helper lipid formulations demonstrated nearly 60% transfection as evidenced by mCherry (+) cells using flow cytometry. We achieved efficient knock-down (KD) when delivering our LNP complexed with siRNA against Bdh1 in primary rat lung MVECs in vitro, in which over 80% KD of Bdh1 expression was achieved (RT-qPCR) when compared to non-targeting siRNA control and normalized to housekeeping gene, Beta-actin. Conclusion: We identified LNP formulations capable of delivering a range of payloads to MVECs. Future work will evaluate the preferential delivery and transfection efficiency of these formulations in vivo to determine the translational utility of metabolite modulation, notably BOHB, in PAH. REFERENCES: 1. Philip, N. et al. Am J Physiol Lung Cell Mol Physiol 326, L252–L265 (2024). 2. Lee, M. H. et al. Am J Physiol Lung Cell Mol Physiol 323, L355–L371 (2022). 3. Cheng, L. et al. ACS nano 18.42, 28735-28747(2024). 4. Zhu, Y. et al. Nat Commun 13.1, 4282 (2022). NSF GRFP DGE2139757 (A.G.), R01HL151530 (K.S.) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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Recent grants

• NIH Grant R21EB015152

  NIH · $437k · 2015

• Biomimetic Matrix for Ex Vivo and In Vivo Activation of T Cells

  NIH · $1.9M · 2020–2025

• Shape Control and Transport Properties of DNA-Copolymer Micelles

  NIH · $1.5M · 2015–2020

• NIH Grant R01GM073937

  NIH · $1.4M · 2013

• NIH Grant R21NS085714

  NIH · $446k · 2017

Frequent coauthors

• Kam W. Leong

  218 shared

• Sami Tuffaha

  Johns Hopkins University

  127 shared

• Ahmet Höke

  Johns Hopkins University

  119 shared

• Chenhu Qiu

  Johns Hopkins University

  113 shared

• Sashank Reddy

  Johns Hopkins Medicine

  98 shared

• Nicholas von Guionneau

  Johns Hopkins University

  88 shared

• Russell Martin

  78 shared

• Yizong Hu

  Massachusetts Institute of Technology

  72 shared

Education

• Postdoctoral Fellow, Department of Biomedical Engineering

  Johns Hopkins School of Medicine

  1998

• Ph.D., Department of Chemistry

  Wuhan University

  1993

• B.S., Department of Chemistry

  Wuhan University

  1988

Awards & honors

• Young Investigator Award at the National University of Singa…
• National Science Foundation Faculty CAREER Award (2008)
• Johns Hopkins University’s Cohen Translational Engineering A…
• Johns Hopkins University’s Cohen Translational Engineering A…
• Louis B. Thalheimer Award for Translational Research (2016)