About

Paul Wender is the Francis W. Bergstrom Professor of Chemistry at Stanford University, with a courtesy appointment in the Department of Chemical and Systems Biology. He earned his B.S. in Chemistry from Wilkes College and his Ph.D. in Chemistry from Yale University in 1973. He was an NIH Postdoctoral Fellow at Columbia University before serving on the faculty at Harvard University. His research group addresses unsolved problems in chemistry, synthesis, biology, medicine, and materials science by utilizing new computational tools, reactions, reagents, strategies, and design. The lab emphasizes the use of chemistry, design, and synthesis to tackle significant biological and medical issues, including the eradication of HIV/AIDS, overcoming resistant cancer, cancer immunotherapy, and treating cognitive disorders such as Alzheimer's disease. Professor Wender's work is supported by affiliations with the Medical School, Imaging Center, Chemical Biology Program, and Molecular Therapeutics Program, along with numerous collaborations. His research has been recognized with numerous awards, including the Tetrahedron Prize, Prelog Medal, Arthur Cope Award, Cohen Award for Excellence in Medicinal Chemistry, and the Research Award of the German Bioactives and Biotechnology Leibniz Alliance. He has also received several teaching awards, such as the Hoagland Prize, Bing Teaching Award, and the Dean's Teaching Award. He is an elected member of the US National Academy of Sciences, a foreign member of the Royal Spanish Academy of Sciences, and a fellow of the American Association for the Advancement of Science and the American Academy of Arts and Sciences.

Research topics

• Biology
• Immunology
• Virology
• Medicine
• Biochemistry
• Cell biology
• Neuroscience
• Genetics

Selected publications

• Leveraging HIV-Specific CAR T Cells and Rapamycin Treatment in “Kick-and-Kill” HIV Cure Approaches

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-15

  articleOpen access

  ABSTRACT HIV is not cured with currently available combination antiretroviral therapy (ART) alone in large part because the virus establishes virologic latency in long lived CD4 + cells. To eliminate this latent reservoir, as required for HIV eradication, latency reversing agents (LRAs) are being developed to force HIV out of latency and induce infected cells to express viral proteins leading to their clearance, in a so-called “Kick-and-Kill” approach. This strategy relies on the immune system to clear the productively-infected cells and is thus limited by HIV immune evasion and the immunological exhaustion that occurs during HIV infection. To counter these limitations and augment an LRA-mediated HIV cure approach, we report herein the utility of HIV-specific truncated CD4-based D1D2 CAR T cells combined with LRA treatment and the mTORC1 inhibitor rapamycin to reduce immune exhaustion and specifically target and kill LRA-stimulated HIV infected cells. We demonstrate that rapamycin does not prevent HIV latency reversal via multiple classes of LRAs in several in vitro models, suggesting that it is compatible with cure approaches utilizing these LRAs. Additionally, rapamycin does not inhibit the early T cell activation (CD69 upregulation) in primary T cells that occurs during protein kinase C (PKC) modulator-mediated HIV latency reversal. Furthermore, in vitro chronically exhausted CAR T cells were found to have a higher frequency of terminally exhausted PD-1 + Tim-3 + and CD69 + PD-1 + cells when compared to CAR T cells that were cultured under the same conditions in the presence of rapamycin, validating the use of the mTORC1 inhibitor rapamycin to prevent immune exhaustion of CAR T cells. Finally, we found that latently-infected cells that were stimulated to express HIV proteins using a designed, synthetic PKC modulator LRA (SUW133) were efficiently recognized and killed by CAR T cells. Overall, these data demonstrate the compatibility of immune rejuvenation using rapamycin with HIV reservoir depletion using LRAs and CAR T cells. This combination therapy strategy represents a promising approach to more effectively target the latent reservoir in HIV cure approaches.

  PublisherOA PDFDOI

• Synthesis and preclinical evaluation of tigilanol tiglate analogs as latency-reversing agents for the eradication of HIV

  Science Advances · 2025-01-24 · 2 citations

  articleOpen accessSenior authorCorresponding

  Tigilanol tiglate (EBC-46) is a selective modulator of protein kinase C (PKC) isoforms that is Food and Drug Administration (FDA) approved for the treatment of mast cell tumors in canines with up to an 88% cure rate. Recently, it has been FDA approved for the treatment of soft tissue sarcomas in humans. The role of EBC-46 and, especially, its analogs in efforts to eradicate HIV, treat neurological and cardiovascular disorders, or enhance antigen density in antigen-targeted chimeric antigen receptor-T cell and chimeric antigen receptor-natural killer cell immunotherapies has not been reported. Enabled by our previously reported scalable synthesis of EBC-46, we report herein the systematic design, synthesis, and evaluation of EBC-46 analogs, including those inaccessible from the natural source and their PKC affinities, ability to translocate PKC, nuclear factor κB activity, and efficacy in reversing HIV latency in Jurkat-Latency cells. Leading analogs show exceptional PKC affinities, isoform selectivities, and functional activities, serving as promising candidates for therapeutic applications.

  PublisherDOI

• <i>In Vivo</i> mRNA Delivery to the Lung Vascular Endothelium by Dicationic Charge-Altering Releasable Transporters

  Journal of the American Chemical Society · 2025-10-21 · 2 citations

  articleOpen access

  Endothelial cells (ECs) comprise the pulmonary vascular bed and play a significant role in health and diseases. Consequently, the EC niche represents an attractive therapeutic target for treating a wide range of pulmonary vascular diseases. We have identified a new class of dicationic charge-altering releasable transporters. These single-component transporters selectively deliver mRNA to the lung upon intravenous administration without the use of a targeting ligand. Significantly, the number and spatial array of cationic charges within the repeating units of the CART polymer are found to control both mRNA delivery efficacy and tissue tropism. High-resolution imaging revealed efficient mRNA delivery to endothelial cells in pulmonary arteries, veins, and capillaries. The selective lung tropism of these new CARTs, coupled with the efficient and tunable synthesis of this new family of CART amphiphiles, represents an enabling platform for research and clinical applications.

  PublisherOA PDFDOI

• Correlations among quantitative assays that measure the size of HIV reservoirs in people with HIV receiving antiretroviral therapy

  AIDS · 2025-09-25

  article
  PublisherDOI

• Next-generation materials for nucleic acid delivery

  Nature Reviews Materials · 2025-06-16 · 30 citations

  reviewOpen access
  PublisherOA PDFDOI

• Discrete Immolative Guanidinium Transporters deliver mRNA to specific organs and red blood cells

  Nature Communications · 2025-08-01 · 3 citations

  articleOpen accessSenior author

  RNA medicine is an emerging groundbreaking technology for the prevention and treatment of disease. However, tools to deliver messenger RNA (mRNA) and other polyanions (circRNA, saRNA, pDNA, CRISPR-Cas, reprogramming factors) are required to advance current RNA therapies and address next generation challenges. Existing delivery systems often suffer from laborious syntheses, limited organ selectivity, formulation complexity, and undesired inflammatory responses. Here, we report novel mRNA delivery systems termed Discrete Immolative Guanidinium Transporters (DIGITs), which are synthesized convergently in as few as 4 steps. Unlike most cationic (ammonium) delivery systems, DIGITs are based on cationic guanidinium moieties, which complex mRNA at acidic pH and undergo irreversible neutralization at physiological pH to enable efficient RNA release. Systematic evaluation of structural variations and formulations have led to DIGIT/mRNA complexes that selectively target lung, spleen, and immature red blood cells in peripheral blood in female mice model. DIGIT/mRNA delivery systems show minimal toxicity based on cell viability and biochemical assays, supporting their future utility in biomedical applications. mRNA-based therapies require efficient and selective delivery systems to advance clinical applications and overcome challenges posed by current formulations. Here, authors developed Discrete Immolative Guanidinium Transporters (DIGITs), chemically defined carriers that enable pHresponsive mRNA release with organ and reticulocyte selectivity, minimal toxicity, and scalable synthesis.

  PublisherOA PDFDOI

• <i>In vivo</i> mRNA delivery to the lung vascular endothelium by dicationic Charge-Altering Releasable Transporters

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-19

  preprintOpen access

  Abstract Endothelial cells (EC) comprise the pulmonary vascular bed and play a significant role in health and disease. Consequently, the EC niche represents an attractive therapeutic target for treating a wide range of pulmonary vascular diseases. We have identified a new class of dicationic Charge-Altering Releasable Transporters. These single-component transporters selectively deliver mRNA to the lung upon intravenous administration without the use of a targeting ligand. Significantly, the number and spatial array of cationic charges within the repeating units of the CART polymer are found to control both mRNA delivery efficacy and tissue tropism. High-resolution imaging revealed efficient mRNA delivery to endothelial cells in pulmonary arteries, veins and capillaries. The selective lung tropism of these new CARTs, coupled with the efficient and tunable synthesis of this new family of CART amphiphiles, represents an enabling platform for research and clinical applications.

  PublisherOA PDFDOI

• Organ- and Cell-Selective Delivery of mRNA In Vivo Using Guanidinylated Serinol Charge-Altering Releasable Transporters

  Journal of the American Chemical Society · 2024-05-14 · 33 citations

  articleOpen accessSenior authorCorresponding

  Selective RNA delivery is required for the broad implementation of RNA clinical applications, including prophylactic and therapeutic vaccinations, immunotherapies for cancer, and genome editing. Current polyanion delivery relies heavily on cationic amines, while cationic guanidinium systems have received limited attention due in part to their strong polyanion association, which impedes intracellular polyanion release. Here, we disclose a general solution to this problem in which cationic guanidinium groups are used to form stable RNA complexes upon formulation but at physiological pH undergo a novel charge-neutralization process, resulting in RNA release. This new delivery system consists of guanidinylated serinol moieties incorporated into a charge-altering releasable transporter (GSer-CARTs). Significantly, systematic variations in structure and formulation resulted in GSer-CARTs that exhibit highly selective mRNA delivery to the lung (∼97%) and spleen (∼98%) without targeting ligands. Illustrative of their breadth and translational potential, GSer-CARTs deliver circRNA, providing the basis for a cancer vaccination strategy, which in a murine model resulted in antigen-specific immune responses and effective suppression of established tumors.

  PublisherOA PDFDOI

• 3.2 – 00080 New PKC Modulator Latency Reversing Agents for depleting persistent HIV reservoirs

  Journal of Virus Eradication · 2024-12-01

  articleOpen access
  PublisherDOI

• Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells

  Pathogens and Immunity · 2024-04-24 · 2 citations

  articleOpen access

  Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells. Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. Conclusions: T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the "kick" rather than the "kill" arm of this HIV cure approach.

  PublisherOA PDFDOI

Recent grants

• Functional Materials Through Synthesis Informed Design

  NSF · $585k · 2019–2022

• New Materials to Deliver mRNA: Applications in Cancer Immunotherapy

  NIH · $2.1M · 2020–2025

• Synthetic Studies Related to Cancer Research/Treatment

  NIH · $12.8M · 1981–2027

• New Materials to Deliver mRNA: Applications in Cancer Immunotherapy

  NIH · $512k · 2020–2025

• NIH Grant R37CA031841

  NIH · $2.1M · 2000

Frequent coauthors

• Kazuhiro Irie

  Doshisha University

  52 shared

• Hajime Ohigashi

  42 shared

• Robert M. Waymouth

  Stanford University

  42 shared

• Zhi‐Xiang Yu

  Beijing National Laboratory for Molecular Sciences

  40 shared

• Susan L. Mooberry

  The University of Texas Health Science Center at San Antonio

  29 shared

• K. N. Houk

  University of California, Los Angeles

  29 shared

• Jonathan B. Rothbard

  Stanford University

  28 shared

• Gabriel G. Gamber

  Novartis (United States)

  28 shared

Awards & honors

• Tetrahedron Prize
• Prelog Medal (Swiss Federal Institute of Technology)
• Arthur Cope Award (American Chemical Society)
• Cohen Award for Excellence in Medicinal Chemistry (Israel Ch…
• Research Award of the German Bioactives and Biotechnology Le…