About

W. Mark Saltzman is a Sterling Professor of Biomedical Engineering at Yale University, with additional appointments in Chemical & Environmental Engineering, Materials Science, Cellular & Molecular Physiology, and Dermatology. His research is motivated by the desire to create safer and more effective medical and surgical therapies, focusing on tissue engineering and drug delivery methods. His group has developed technology based on biocompatible polymeric materials for the controlled delivery of drugs, proteins, and genes, as well as new polymeric materials that influence tissue growth and assembly. Saltzman aims to develop economical, transportable, and accessible methods for disease prevention, emphasizing the importance of prevention over treatment. He is committed to training a new generation of chemical and biomedical engineers in a stimulating and collaborative environment that promotes the exchange of ideas and the integration of technology with modern biological science.

Research topics

• Biology
• Computational biology
• Biochemistry
• Chemistry
• Computer Science
• Medicine
• Materials science
• Biotechnology
• Pharmacology
• Nanotechnology
• Virology
• Microbiology
• Immunology
• Cancer research
• Genetics
• Internal medicine
• Data science

Selected publications

• Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver

  Biochemistry · 2025-03-24 · 7 citations

  reviewSenior authorCorresponding

  Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.

  PublisherDOI

• Systemic in utero gene editing as a treatment for cystic fibrosis

  Proceedings of the National Academy of Sciences · 2025-06-10 · 4 citations

  articleOpen accessCorresponding

  In utero gene editing has the potential to modify disease-causing genes in multiple developing tissues before birth, possibly allowing for normal organ development, disease improvement, and conceivably, cure. In cystic fibrosis (CF), a disease that arises from mutations in the CF transmembrane conductance regulator ( CFTR ) gene, there are signs of multiorgan disease affecting the function of the respiratory, gastrointestinal, and reproductive systems already present at birth. Thus, treating CF patients early is crucial for preventing or delaying irreversible organ damage. Here, we demonstrate proof-of-concept of multiorgan mutation correction in CF using peptide nucleic acids encapsulated in polymeric nanoparticles and delivered systemically in utero. In utero editing was associated with sustained postnatal CFTR activity, at a level similar to that of wild-type mice, in both respiratory and gastrointestinal tissues, without detection of off-target mutations in partially homologous loci. This work suggests that systemic in utero gene editing represents a viable strategy for treating monogenic diseases before birth that impact multiple tissue types.

  PublisherDOI

• Fertile Ground for Mathematical Modeling: Therapeutic and Diagnostic Nanoparticle Transport in the Glomerulus

  Regenerative Engineering and Translational Medicine · 2025-06-02

  articleSenior author
  PublisherDOI

• Mosaic pattern: lung functional heterogeneity at the alveolus level

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-14

  preprintOpen access

  Inhaled particles carrying pathogens, pollutants (e.g., microplastics, smoke), therapeutics, and diagnostics are increasingly relevant to public health, yet real-time tracking of aerosol transport in functional alveoli remains challenging. Here, we used the recently developed crystal ribcage to investigate aerosol transport in ex vivo lungs during active ventilation, obtaining the first real-time observations of single aerosol droplet transport and deposition in functional alveoli. We discovered deterministic heterogeneity at both intra- and inter-alveolar levels, with aerosol distribution forming a characteristic "mosaic" pattern in which only specific alveolar clusters received particles. The pattern was consistently formed in vivo during spontaneous breathing and ex vivo using both positive- and negative-pressure ventilation. This pattern was also consistent across a range of aerosols, including small molecules, nanobodies, nanoparticles, microplastics, therapeutics, and pathogens. Additionally, the pattern was observed in murine, porcine, and human lungs, and evolved from birth through aging in mice. The post-deposition stability of the pattern depended on particle type and lung age, lasting from a few minutes for small molecular weight particles to multiple days for cell-binding particles. These alveolar-level heterogeneities may uncover previously unrecognized biological and immunological heterogeneities associated with the mosaic pattern, including its role in postnatal lung development, susceptibility to inhaled airborne hazards such as pollutants and infectious agents, and early pathogenesis and response to inhaled therapeutics in respiratory diseases such as pneumonia, COPD, asthma, and lung cancer.

  PublisherOA PDFDOI

• Abstract A100: Systemic targeting of therapeutic RNA into pancreatic tumors via an RNA-binding and cell-penetrating antibody

  Cancer Research · 2025-09-28

  article

  Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, in large part due to its high resistance to immunotherapies. PDAC is an unresponsive immunological tumor due to low frequency of neoantigens, the immunosuppressive microenvironment, the highly desmoplastic stroma, and low vascularity, all of which highly limit the infiltration of immune cells and therapeutic drugs. Thus, conventional and current approaches, such as immune checkpoint blockades, have shown minimal benefit for PDAC treatment, highlighting the urgent need to develop new therapeutic strategies to reprogram the tumor microenvironment and activate an effective antitumor immune response. We developed TMAB3, engineered from the lupus-derived antibody 3E10, capable of non-covalently binding and protecting RNAs for systemic tumor-targeted delivery. TMAB3 binds RNA with high affinity via a modified nucleic acid-binding pocket and selectively penetrates tumor cells by engaging the ENT2 nucleoside transporter, which is upregulated in PDAC and other malignancies. We complexed TMAB3 with 3p-hpRNA, an immunogenic RNA that activates RIG-I, a cytosolic sensor of viral RNA, triggering type I interferon responses and downstream antitumor immunity. In this study, we demonstrate that the intravenous administration of TMAB3/3p-hpRNA complexes specifically targets malignant cells within PDAC tumors in mice, significantly reduces tumor growth, and triples animal survival after only three acute doses. Furthermore, in orthotopic PDAC, we demonstrate that treatment with TMAB3/3p-hpRNA complexes mechanistically enhances intratumoral CD8+ T cell infiltration and activation, promotes the expression of interferon-stimulated genes, and shifts the immune landscape toward an activated phenotype. Notably, these therapeutic effects were reversed in T cell-deficient (Rag1 knockout) mice, confirming that efficacy depends on adaptive immunity and immunogenic tumor cell death. Additionally, single-cell RNA sequencing of the TMAB3/3p-hpRNA-treated PDAC tumors showed a reduction in malignant cells, upregulation of apoptotic genes, and increase expression of genes associated with an effective and active T cell response. In vitro co-culture experiments also showed that effective T cell activation required tumor cell expression of both ENT2 and RIG-I, highlighting the tumor-specific mechanism of action. Together, these findings introduce TMAB3 as a novel antibody-based platform for the systemic delivery of immunostimulatory RNAs to immunologically quiescent tumors. This strategy overcomes key delivery and immunogenicity barriers in PDAC, thereby unlocking the potential of RNA-based immunotherapies for cancers that are traditionally unresponsive to immune intervention. Citation Format: Diana Martinez-Saucedo, Elias Quijano, Zaira Ianniello, Natasha Pinto Medici, Madison Rackear, Haoting Chen, Luiz Lola-Pereira, Yanfeng Liu, Denise Hegan, Xinning Shan, Robert Tseng, Deanne Yugawa, Sumedha Chowdhury, Minsoo Khang, Wendy S. Woods, Nicholas Gosstola, Ranjit S. Bindra, Marie E. Robert, David A. Braun, Pablo Perez Pinera, W Mark. Saltzman, Luisa F. Escobar-Hoyos, Peter M. Glazer. Systemic targeting of therapeutic RNA into pancreatic tumors via an RNA-binding and cell-penetrating antibody [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A100.

  PublisherDOI

• Endothelial cell MHC molecules are necessary and sufficient to reject 3D-printed human skin grafts in an advanced human immune system mouse

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-25

  preprintOpen access

  Vascularized skins were 3D-printed using single donor human fibroblasts, pericytes, keratinocytes and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks post-grafting with human peripheral blood mononuclear cells (PBMCs) autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells, and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection despite MHC molecule expression on other graft cell types.

  PublisherOA PDFDOI

• Investigation of the protein corona and biodistribution profile of polymeric nanoparticles for intra-amniotic delivery

  Biomaterials · 2025-03-06 · 6 citations

  articleSenior authorCorresponding
  PublisherDOI

• Systemic administration of an RNA binding and cell-penetrating antibody targets therapeutic RNA to multiple mouse models of cancer

  Science Translational Medicine · 2025-07-16 · 6 citations

  article

  There is intense interest in the advancement of RNAs as rationally designed therapeutic agents, especially in oncology, where a major focus is to use RNAs to stimulate pattern recognition receptors to leverage innate immune responses. However, the inability to selectively deliver therapeutic RNAs within target cells after intravenous administration now hinders the development of this type of treatment for cancer and other disorders. Here, we found that a tumor-targeting, cell-penetrating, and RNA binding monoclonal antibody, TMAB3, can form stable, noncovalent antibody/RNA complexes of a discrete size that mediate highly specific and functional delivery of RNAs into tumors. Using 3p-hpRNA, an agonist of the pattern recognition receptor retinoic acid-inducible gene-I (RIG-I), we observed robust antitumor efficacy of systemically administered TMAB3/3p-hpRNA complexes in mouse models of pancreatic cancer, medulloblastoma, and melanoma. In the KPC syngeneic, orthotopic pancreatic cancer model in immunocompetent mice, treatment with TMAB3/3p-hpRNA tripled animal survival, decreased tumor growth, and specifically targeted malignant cells, with a 1500-fold difference in RNA delivery into tumor cells versus nonmalignant cells within the tumor mass. Single-cell RNA sequencing (scRNA-seq) and flow cytometry demonstrated that TMAB3/3p-hpRNA treatment elicited a potent antitumoral immune response characterized by RIG-I activation and increased infiltration and activity of cytotoxic T cells. These studies established that TMAB3/RNA complexes can deliver RNA payloads specifically to hard-to-treat tumor cells to achieve antitumor efficacy, providing an antibody-based platform to advance the study of RNA therapies for the treatment of patients with cancer.

  PublisherDOI

• Cellular determinants influence the red blood cell adsorption efficiency of poly(amine- <i>co</i> -ester) nanoparticles

  Science Advances · 2025-05-02 · 5 citations

  articleOpen accessSenior authorCorresponding

  -ester) (PACE) nanoparticles, drug delivery vehicles for nucleic acid and small molecule cargoes, accumulate in the liver and spleen following intravenous administration, limiting delivery to nonhepatosplenic tissues. Red blood cell (RBC) hitchhiking, a strategy in which nanoparticles are nonspecifically adsorbed to RBCs prior to administration, has been used to modulate nanoparticle biodistribution, enabling enrichment in organs immediately downstream from the site of vascular infusion. We find that scarcely investigated cellular determinants-namely, storage duration, membrane stiffness, and membrane-bound sialic acid quantity-substantially affect PACE nanoparticle adsorption efficiency. Following development of an optimized adsorption protocol, RBC hitchhiking was shown to enhance PACE nanoparticle cargo delivery to pulmonary tissue while also increasing exposure to other assayed organs. These findings inform future RBC hitchhiking study design, implicate cellular variables as potential obstacles or boons to clinical translation, and demonstrate the delivery of nucleic acids using this strategy with the PACE nanoparticle platform.

  PublisherDOI

• Biodistribution of Polymeric Nanoparticles following in utero Delivery to a Nonhuman Primate

  Biomedicine Hub · 2024-12-12 · 1 citations

  articleOpen access

  Introduction: Monogenic diseases can be diagnosed before birth. Systemic fetal administration of nanoparticles (NPs) grants therapeutic access to developing stem cell populations impacted by these classes of disease. Delivery of editing reagents in these NPs administered before birth has yielded encouraging results in preclinical mouse models of monogenic diseases. Methods: To translate this strategy clinically, the safety and efficacy of this strategy in larger animals will be necessary. We performed a pilot biodistribution study in 3 fetal nonhuman primates (NHPs) in mid-gestation examining systemic delivery of polymeric NPs loaded with fluorescent dye. Results: We found several similarities in distribution to our experience in mice, namely, extensive uptake in fetal liver and spleen. A striking finding that is not recapitulated in the mouse was the accumulation of NPs in the zones of proliferation and ossification of the fetal bone. Of great importance, there did not appear to be NP accumulation in the fetal male or female germline zones or maternal tissue. Conclusion: These studies were vital to the next step of testing editing reagents in the fetal NHP with a goal of treating monogenic diseases before birth.

  PublisherDOI

Recent grants

• NIH Grant T32DK101019

  NIH · $1.2M · 2019

• NIH Grant R01DE014097

  NIH · $1.4M · 2007

• Nonenzymatic Gene Editing in Treatment of Heredity Spherocytosis

  NIH · $2.4M · 2019–2023

• Manipulation of Cell Behavior in Three-Dimensional Culture

  NSF · $212k · 1992–1995

• Ex Vivo Nanoparticle Drug Delivery Targeted to Human Renal Allograft Endothelium

  NIH · $2.2M · 2017–2023

Frequent coauthors

• Peter M. Glazer

  42 shared

• Ranjit S. Bindra

  41 shared

• Hee‐Won Suh

  Dartmouth College

  36 shared

• Jordan S. Pober

  Yale University

  36 shared

• Christopher J. Cheng

  35 shared

• Elias Quijano

  Yale University

  34 shared

• Alexandra S. Piotrowski-Daspit

  28 shared

• Carmen J. Booth

  Yale University

  24 shared

Education

• Ph.D., Medical Engineering

  Massachusetts Institute of Technology

  1987

• S.M., Chemical Engineering

  Massachusetts Institute of Technology

  1984

• B.S., Chemical Engineering

  Iowa State University

  1981

Awards & honors

• Elected Member, National Academy of Engineering (2018)
• Founders Award, Controlled Release Society (2017)
• Chemical and Biological Engineering Hall of Fame, Iowa State…
• Elected Member, National Academy of Medicine (formerly Insti…
• Mines Medalist, South Dakota School of Mines (2014)