Biology subjects

Artzi, N.

Publications and source records attributed to Artzi, N..

4 recordsLinked to original sources

bioRxiv2026

Enhanced lung delivery of an immunostimulatory duplex RNA augments the antitumor activity by reshaping systemic cytokine pharmacodynamics

The organ-specific enrichment of drug delivery vehicles, such as lipid nanoparticles (LNPs), can be leveraged to concentrate drugs at disease sites to increase efficacy and limit toxicity. For immunostimulatory therapeutics, however, tissue accumulation beyond diseased sites may also shape drug activity by determining which organs and cell populations first sense the agonist and initiate downstream immune responses. Here, we show that the anticancer efficacy of an immunostimulatory duplex RNA (dsRNA) can be augmented using LNPs that are formulated to preferentially target the lung, which dictates the systemic pharmacodynamics of the cytokines it elicits. The immunostimulatory dsRNA was formulated into LNPs engineered for either enhanced liver-(LiverLNPs) or lung-(LungLNPs) based delivery, matched for size, encapsulation efficiency, and in vitro potency. In mice, delivery of dsRNA in LungLNPs enhanced uptake into endothelial, epithelial, and resident immune cells populations and induced substantially higher circulating levels of type I, type III interferons and proinflammatory cytokines than dsRNA formulated in LiverLNPs. This significant systemic response induced by lung-enhanced delivery required competent retinoic acid-inducible gene I and Toll-like receptor 7 signaling. Functionally, LNPs that preferentially targeted the lungs induced significantly greater suppression of tumor growth in both subcutaneous and metastatic models of melanoma. LungLNP/dsRNA also induced cytokine secretion and inhibited tumor cell proliferation in a human lung cancer-on-a-chip model. Together, these results establish that pulmonary exposure can alter systemic pharmacodynamics and therapeutic activity of immunostimulatory RNA.

bioengineering↗

bioRxiv2025

Injectable adhesive hydrogel-drug complexes synchronize the release of chemoimmunotherapy to treat brain tumors in mice

Brain tumor therapy remains limited by an immunosuppressive, monotherapy-resistant tumor microenvironment and by a paucity of technologies capable of controlling therapy delivery kinetics to the tumor. Here, we describe tissue-adhesive hydrogel-drug complexes (HDCs) for the controlled release of combination therapies synchronized with immune cycle responses following intracranial administration. Injected adhesive HDCs enabled the controlled co-delivery of multiple payloads (chemotherapy, stimulator of interferon genes agonist cyclic dinucleotide nanoparticles, immune checkpoint blockade antibodies), leading to enhanced long-term survival (>80%) and protection from contralateral hemisphere rechallenge after a single dose in multiple syngeneic orthotopic glioblastoma mouse models. Mechanistic studies revealed that tumor rejection is a consequence of reprogramming the tumor microenvironment, driven by three key phases: the initial rapid expression of inflammatory cytokines, notably IFN-{gamma}, and tumor sensitization with antigen exposure during chemoimmunotherapy release, followed by the recruitment and subsequent sustained activation of antigen-presenting and effector cells facilitated by the hydrogels multiweek delivery period. These findings point to tissue-adhesive HDCs, and therapeutic release synchronized with biological responses as key considerations for realizing robust immune activation without provoking toxicity in the treatment of solid tumors.

bioengineering↗

bioRxiv2022

Localized nanoparticle-mediated delivery of miR-29b normalises the dysregulation of bone homeostasis caused by osteosarcoma whilst simultaneously inhibiting tumour growth.

Patients diagnosed with osteosarcoma undergo extensive surgical intervention and chemotherapy resulting in dismal prognosis and compromised quality of life owing to poor bone regeneration, which is further compromised with chemotherapy delivery. This study aims to investigate if localised delivery of miR-29b--which has been shown to promote bone formation by inducing osteoblast differentiation and also to suppress prostate and glioblastoma tumour growth--would suppress osteosarcoma tumours whilst simultaneously normalising the dysregulation of bone homeostasis caused by osteosarcoma. Thus, we studied the therapeutic potential of miR-29b to promote bone remodelling in an orthotopic model of osteosarcoma (rather than in bone defect models using healthy mice), and in the context of chemotherapy, that is clinically relevant. We developed a formulation of miR-29b:nanoparticles that were delivered via a novel hyaluronic-based hydrogel to enable local and sustained release of the therapy, and to study the potential of attenuating tumour growth whilst normalising bone homeostasis. We found that when miR-29b was delivered along with systemic chemotherapy, compared to chemotherapy alone, our therapy provided a significant decrease in tumour burden, increase in mouse survival, and a significant decrease in osteolysis thereby normalising the dysregulation of bone lysis activity caused by the tumour.

bioengineering↗

bioRxiv2020

The Landscape of Precision Cancer Combination Therapy: A Single-Cell Perspective

The availability of single-cell transcriptomics data opens new opportunities for rational design of combination cancer treatments. Mining such data, we employed combinatorial optimization techniques to explore the landscape of optimal combination therapies in solid tumors including brain, head and neck, melanoma, lung, breast and colon cancers. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. As a baseline case, we studied the killing of at least 80% of the tumor cells while sparing more than 90% of the non-tumor cells in each patient, as a putative regimen. We find that in most cancer types, personalized combinations composed of at most four targets are then sufficient. However, the number of distinct targets that one would need to assemble to treat all patients in a cohort accordingly would be around 10 in most cases. Further requiring that the target genes be also lowly expressed in healthy tissues uncovers qualitatively similar trends. However, as one asks for more stringent and selective killing beyond the baseline regimen we focused on, we find that the number of targets needed rises rapidly. Emerging individual promising receptor targets include PTPRZ1, which is frequently found in the optimal combinations for brain and head and neck cancers, and EGFR, a recurring target in multiple tumor types. In sum, this systematic single-cell based characterization of the landscape of combinatorial receptor-mediated cancer treatments establishes first of their kind estimates on the number of targets needed, identifying promising ones for future development.

bioinformatics↗