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Kaskow, J. A.

Publications and source records attributed to Kaskow, J. A..

2 recordsLinked to original sources
bioRxiv2026

Engineering nanoparticle surface chemistry for antigen-presenting cell targeting improves specificity and safety of TLR3 agonist cancer immunotherapy

Innate immune agonists are promising therapeutic agents to induce immune responses against cancer. However, these agents have been limited by toxicity associated with systemic accumulation and activity in off-target cells. In this work, a targeted nanoparticle (NP) platform to encapsulate and protect the Toll-like receptor 3 (TLR3) agonist polyinosinic-polycytidylic acid (poly(I:C)) and promote its specific delivery to antigen presenting cells (APCs), macrophages and dendritic cells, for activation of this cell population was designed. To determine NP physiochemical properties that promote APC delivery, we developed a library of NP surface chemistries formed by electrostatic adsorption of polyanion coatings onto liposomes using layer-by-layer (LbL) assembly and screened the particles on APCs and off-target cells. Dextran sulfate was identified as a promising coating to enhance specific APC delivery. We applied these design parameters to develop a poly(I:C)-loaded NP for an APC-targeted immunotherapy. In a model of metastatic ovarian cancer, the LbL NP prolonged poly(I:C) retention in the peritoneal space--with 2-fold remaining 24-48hr after administration compared to free poly(I:C)--ultimately reducing systemic accumulation and associated toxicities. Compared to free drug, the NP reduced the increase in serum levels of TNF, IL-6, and CXCL10 by 9-, 4-, and 31-fold respectively. NP-treated mice experienced lower weight loss and recovered more quickly at a higher poly(I:C) dose, indicating a widening of the therapeutic window. The NP formulation enhanced accumulation of poly(I:C) in the tumor 2-fold and activation of the target APC population compared to free drug, and ultimately slowed tumor growth and extended survival in combination with doxorubicin chemotherapy. Overall, this work demonstrates a modular NP delivery strategy to improve the delivery, safety, and therapeutic window of a TLR3 agonist.

bioengineering↗
bioRxiv2026

A Multivalent Peptide-Polymer Conjugate Material Mimics STING to Therapeutically Activate Innate Immune Signaling

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.

bioengineering↗