About

Paula T. Hammond is an Institute Professor and Dean of the School of Engineering at MIT. She holds the title of Institute Professor and is recognized for her leadership in the field of chemical engineering. Her research focuses on areas related to chemical engineering, including biomedical and biotechnology, catalysis and reaction engineering, energy, environment and sustainability, materials, math and computational systems, and transport and thermodynamics. Hammond's work contributes significantly to advancing knowledge and innovation in these areas, and she is a prominent figure within the MIT Department of Chemical Engineering.

Research topics

• Chemistry
• Computer Science
• Materials science
• Biology
• Nanotechnology
• Biomedical engineering
• Medicine
• Cell biology
• Computational biology
• Genetics
• Pharmacology
• Biochemistry

Selected publications

• Polyelectrolyte nanoparticles enable intracellular delivery of STING protein fragments for ovarian cancer immunotherapy

  Materials Today Bio · 2026-05-01

  articleOpen accessSenior authorCorresponding

  ABSTRACT Therapeutic activation of stimulator of interferon genes (STING) signaling shows promise as a method of inflaming the tumor microenvironment to generate an anti-cancer immune response. Frequent loss of STING expression in many human cancers renders small-molecule agonists ineffective in cancer cells. We previously demonstrated that delivering a fragment of the STING protein, dubbed STINGΔTM, to the cytosol can bypass this challenge by directly activating downstream signaling molecules in the cytosol; however, this strategy requires an effective cytosolic protein delivery vehicle to be therapeutically active. In this work, we develop a poly(β-amino ester) (PBAE) degradable polycation nanoparticle formulation to target ovarian cancer and deliver bioactive STINGΔTM protein to the cytosol. Screening experiments reveal that increasing PBAE hydrophobicity enables efficient protein encapsulation and delivery to the cytosol. We then develop a pH-shift-mediated method to assemble smaller, negatively charged nanoparticles composed of STINGΔTM protein, PBAE, and a polyanion. The polyanion can tune the cell type specificity of STING signaling activation in vitro , with poly(L-glutamate) and poly(L-aspartate) preferentially activating signaling in ovarian cancer cells. In a syngeneic mouse model of ovarian cancer, nanoparticles accumulate preferentially in tumors throughout the abdomen, slow tumor growth, and extend survival. Overall, the development of a tumor-targeted PBAE nanoparticle enabled the treatment of ovarian cancer through the direct intracellular delivery of STING protein, yielding an immunotherapy that shows promise for the treatment of cancers with dysregulated STING.

  PublisherDOI

• A multivalent peptide-polymer conjugate material mimics STING to therapeutically activate innate immune signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-26

  articleOpen accessSenior authorCorresponding

  Stimulator of interferon genes (STING) is a promising therapeutic target for cancer immunotherapy, but agonists are often rendered ineffective by the loss of STING expression in cancer cells. Here we engineer a multivalent peptide-polymer conjugate material that can easily be delivered to the cytosol, where it mimics key protein interactions from the missing STING protein to directly activate downstream innate immune signaling. While previously developed STING mimicking therapeutics use nearly the full STING protein, this material contains only a 39 amino acid peptide from the STING C-terminal tail that includes interaction motifs for downstream kinase TBK1 and transcription factor IRF3. Conjugation of multiple peptide copies to a negatively charged polymer backbone mimics the multivalent protein-protein interactions of the oligomerized STING signaling complex, activating TBK1 and IRF3 as well as the transcription of downstream genes in both STING-proficient and STING-silenced cancer cell lines. We optimize a lipid nanoparticle formulation to deliver this conjugate material intracellularly, allowing for its application as an immunotherapy for ovarian cancer. Treatment with the STING mimicking conjugate material promoted the production of type I interferons, repolarization of myeloid cells to an anti-tumor phenotype, and recruitment of T cells to tumors in mice. This treatment ultimately led to tumor regression and extended survival in multiple mouse models of metastatic ovarian cancer. Overall, this work highlights the potential of peptide-polymer conjugate mimics of STING to therapeutically activate innate immune signaling.

  PublisherOA PDFDOI

• Carriers Multimerize STING Protein Fragments to Activate Type I Interferon Signaling in STING-Deficient Cancer Cells

  Molecular Pharmaceutics · 2025-07-07 · 1 citations

  articleSenior authorCorresponding

  Therapeutic activation of the stimulator of interferon genes (STING) innate immune pathway shows promise for cancer immunotherapy; however, frequent loss of STING expression in cancer cells renders these cells unresponsive to existing agonists. We report that cytosolic delivery of a soluble STING protein fragment bypasses this challenge by interacting directly with downstream signaling molecules TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) to activate a Type I interferon response, even in STING-deficient cells. Prior work demonstrated that this same STING fragment was not capable of activating signaling when overexpressed, leading us to investigate how the cytosolic delivery of the protein enables activity. Our results suggest that in addition to facilitating transport across the cell membrane, complexation by delivery vehicles can promote multimerization of the STING fragment, allowing it to remain in a multimeric active state even after escape from the cytosol. Activity remains even after truncation or unfolding of STING's crystallizable domain containing the interface of the protein involved in full-length STING oligomerization, showing that multimerization of STING fragments can proceed by nontypical means. Finally, we demonstrate that this strategy can induce a type I interferon response in multiple STING-proficient and -deficient cancer cell lines. Overall, this work shows how delivery vehicles can be used to modify a protein therapeutic into an active state and provides a proof of concept motivating further development of STING fragment delivery as an immunotherapy.

  PublisherDOI

• Modular Layer-by-Layer Nanoparticle Platform for Hematopoietic Progenitor and Stem Cell Targeting

  ACS Nano · 2025-03-13 · 8 citations

  articleSenior authorCorresponding

  Effective delivery of drug and gene cargos to hematopoietic stem and progenitor cells (HSPCs) is a major challenge. Current therapeutic strategies in genetic disorders or hematological malignancies are hindered by high costs, low accessibility, and high off-target toxicities. Layer-by-layer nanoparticles (LbL NPs) are modular systems with tunable surface properties to enable highly specific targeting. In this work, we developed LbL NPs that target HSPCs via antibody functionalization with reduced off-target uptake by circulating myeloid cells. NPs layered with poly(acrylic acid), a bioinert polymer, provided more stealth properties in vivo than other tested bioactive polyanions. The additional conjugation of anti-cKit and anti-CD90 antibodies improved NP uptake by 2- to 3-fold in nondifferentiated bone marrow cells in vitro. By contrast, anti-CD105 functionalized NPs showed the highest association to HSPCs in vivo, ranging from 3.0 to 8.5% in progenitor subpopulations. This LbL NP platform was then adapted to target human HSPC receptors, with similar targeting trends in healthy CD34+ human cells. By contrast, anti-CXCR4 functionalization demonstrated the greatest targeting to human B-cell lymphoma and leukemia cells. Taken together, these results underscore the therapeutic potential of this modular LbL NP platform with the capacity to target HSPCs in a disease-dependent context.

  PublisherDOI

• Understanding the role of PEGylation on PAMAM’s drug delivery properties to articular cartilage

  SSRN Electronic Journal · 2025-01-01

  preprintOpen accessSenior author
  PublisherDOI

• High‐Throughput Microfluidic‐Mediated Assembly of Layer‐By‐Layer Nanoparticles

  Advanced Functional Materials · 2025-04-03 · 15 citations

  articleOpen accessSenior authorCorresponding

  Surface modification of nanoparticles (NPs) via the layer-by-layer (LbL) technique is a promising approach to generate targeted drug delivery vehicles. LbL-NPs have been successfully used in preclinical models for controlled drug release, tumor and immune cell targeting, improved pharmacokinetics and biodistribution, and controlling cellular trafficking and uptake mechanisms. A simple and scalable synthesis method for LbL-NPs that can be adapted for clinical translation is of great interest. Here we present a new method of polymer deposition onto NPs enabled through microfluidic (MCF) mixing. NPs are mixed with polyelectrolytes using commercially available bifurcating mixer MCF cartridges. In addition to increased process robustness, MCF allows for LbL electrostatic assembly using titrated polymer-to-NP weight equivalent ratios where no excess polymer is required to achieve a given LbL layering. Under such conditions, no time-consuming purification is needed, greatly increasing LbL-NP throughput and avoiding the loss of NPs during purification. We demonstrate the utility of this system using IL-12-loaded liposomal NPs which show equivalent efficacy in vitro and in vivo to LbL-NPs generated via traditional lab-scale batch-wise polymer adsorption and tangential flow filtration purification. Moreover, we show that MCF can assemble LbL films of various chemistries and on various NP core substrates.

  PublisherOA PDFDOI

• Leveraging tissue-resident memory T cells for non-invasive immune monitoring via microneedle skin patches

  medRxiv · 2025-03-21 · 1 citations

  preprintOpen access

  Abstract Detecting antigen-specific lymphocytes is crucial for immune monitoring in the setting of vaccination, infectious disease, cancer, and autoimmunity. However, their low frequency and dispersed distribution across lymphoid organs, peripheral tissues, and blood pose challenges for reliable detection. To address this issue, we developed a strategy exploiting the functions of tissue-resident memory T cells (T rm s) to concentrate target circulating immune cells in the skin and then sample these cells non-invasively using a microneedle (MN) skin patch. T rm s were first induced at a selected skin site through initial sensitization with a selected antigen. Subsequently, these T rm s were restimulated by intradermal inoculation of a small quantity of the same antigen to trigger the “alarm” and immune recruitment functions of these cells, leading to accumulation of antigen-specific T cells from the circulation over several days. In mouse models of vaccination, we show that application of MN patches coated with an optimized hydrogel layer for cell and fluid sampling to this skin site allowed effective isolation of thousands of live antigen-specific lymphocytes as well as innate immune cells. In a human subject with allergic contact dermatitis, stimulation of T rm s with allergen followed by MN patch application allowed the recovery of diverse lymphocyte populations that were absent from untreated skin sites. These results suggest that T rm restimulation coupled with microneedle patch sampling can be used to obtain a window into both local and systemic antigen-specific immune cell populations in a noninvasive manner that could be readily applied to a wide range of disease or vaccination settings.

  PublisherOA PDFDOI

• Convection-Enhanced Delivery of Auristatin-Conjugated Layer-by-Layer Nanoparticles for Glioblastoma Treatment

  Journal of the American Chemical Society · 2025-03-10 · 13 citations

  articleSenior authorCorresponding

  Glioblastoma (GBM) has limited treatment options, as the restrictive blood–brain barrier (BBB) prevents most therapeutics from accumulating at sufficient levels in the brain. Convection-enhanced delivery (CED) offers a method for administering therapeutics directly into brain tumor tissue, but free drugs can be cleared rapidly and may be toxic to off-target cells. Drug-loaded nanoparticles (NPs) are a promising platform to prolong the residence time and improve cellular targeting of therapeutics. We designed drug-conjugated NPs comprising a liposomal core modified with a layer-by-layer (LbL) polymer coating to promote tumor penetration, retention, and tumor-selective cellular association. Covalent conjugation of the potent microtubule inhibitor monomethyl auristatin-F (MMAF) to lipid headgroups resulted in striking potency against a range of patient-derived GBM cell lines compared to free MMAF and outperformed an EGFR-targeted antibody–drug conjugate of MMAF under clinical investigation. In vivo, a single CED infusion of LbL-functionalized MMAF NPs in orthotopic GBM-bearing mice displayed improved distribution and retention of both the NPs and the MMAF payload within the tumor. The LbL coating promotes selective uptake by GBM cells and prolongs drug retention, overcoming limitations of rapid clearance associated with traditional CED approaches. This treatment inhibited tumor progression and significantly extended survival compared to free MMAF, MMAF-conjugated liposomes, and an EGFR-MMAF antibody–drug conjugate. This NP platform offers a promising strategy for enhancing local GBM therapy by improving drug exposure within tumors while minimizing systemic toxicity.

  PublisherDOI

• Surface avidity of anionic polypeptide coatings target nanoparticles to cancer-associated amino acid transporters

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-31 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Tumor-targeted drug delivery enhances therapeutic efficacy while minimizing toxicity. Layer-by-layer nanoparticles (LbL-NPs) coated with anionic polypeptides selectively bind to cancer cells, though the mechanisms have been unclear. Here, we integrated in silico and in vitro approaches—including gene expression analysis, receptor inhibition, and AI-based protein modeling—to show that poly(L-glutamate) (PLE)-coated LbL-NPs bind with high avidity to SLC1A5, a glutamine transporter overexpressed in cancer. We also discovered that PLE clusters SLC1A5 on the cell membrane, promoting prolonged cell surface retention. Poly(L-aspartate) (PLD)-coated NPs similarly bind SLC1A5 but also interact with faster internalizing transporters of anionic amino acids. Correlation analyses across cancer cell lines confirmed a strong link between transporter expression and nanoparticle association. These findings demonstrate that dense glutamate or aspartate presentation through electrostatically adsorbed polypeptides enables selective targeting of overexpressed transporters, providing a mechanistic framework for receptor-targeted delivery that leverages metabolic characteristics of a range of solid tumor types.

  PublisherOA PDFDOI

• Polyamines buffer labile iron to suppress ferroptosis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-02 · 1 citations

  preprintOpen access

  Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines function as endogenous buffers of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using genome-wide CRISPR screens, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, GPX4. Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.

  PublisherOA PDFDOI

Recent grants

• Lipodendrisomes: Co-assembly of New Comb-Rod Dendritic Block Copolymers with Lipids for Tailored Functional Vesicles

  NSF · $460k · 2007–2011

• NIH Grant R01EB008082

  NIH · $745k · 2011

• Integrated Genomics and Bioinformatics

  NIH · $37.6M · 1997–2027

• NIH Grant R01AG029601

  NIH · $1.9M · 2012

• Delivery of cytokines for cancer immunotherapy using nanolayer-controlled trafficking of liposomal nanoparticles

  NIH · $2.3M · 2019–2030

Frequent coauthors

• Darrell J. Irvine

  Scripps Research Institute

  162 shared

• Erik C. Dreaden

  Winship Cancer Institute

  92 shared

• Stephen W. Morton

  88 shared

• Kevin E. Shopsowitz

  Vancouver General Hospital

  83 shared

• Stephen Lillie

  83 shared

• Joelle P. Straehla

  77 shared

• Angela M. Belcher

  Massachusetts Institute of Technology

  67 shared

• Michael B. Yaffe

  Massachusetts Institute of Technology

  58 shared

Labs

• MIT ChemEPI

Education

• Ph.D., Chemical Engineering

  Massachusetts Institute of Technology

  1992

• M.S., Chemical Engineering

  Massachusetts Institute of Technology

  1988

• B.S., Chemical Engineering

  University of California, Berkeley

  1986

Awards & honors

• John M. Prausnitz AIChE Institute Lecturer, 2026
• National Medal of Technology and Innovation, 2024
• Othmer Gold Medal, 2024
• Benjamin Franklin Medal in Chemistry, 2024
• James R. Killian Jr. Faculty Achievement Award, 2023-24