Biology subjects

Greco, A. H.

Publications and source records attributed to Greco, A. H..

3 recordsLinked to original sources

bioRxiv2026

Engineering age-adaptive mRNA lipid nanoparticle cancer vaccines via reprogramming systemic gene expression

Lipid nanoparticle (LNP)-based mRNA vaccines have transformed cancer immunotherapy, yet their efficacy in older individuals, who represent the majority of cancer patients, remains poorly understood. Here, we uncover a critical and previously underappreciated barrier to mRNA LNP cancer vaccine performance in aged hosts: impaired systemic transgene expression. Using the SM-102 mRNA LNPs as a benchmark formulation, we show that while local immune activation and antigen presentation at the injection site and draining lymph nodes remain largely intact with age, transgene expression in peripheral organs, including the liver, lungs, and spleen, is markedly reduced. This deficit limits the magnitude and durability of CD8 and CD4 T cell responses and substantially compromises tumour control. Transcriptomic profiling further reveals that attenuated transgene expression parallels broad attenuation of antigen processing, presentation, and activation pathways in immune cells from aged animals, implicating impaired systemic mRNA translation as a central driver of the downstream immune defects and antitumour efficacy loss. Building on these insights, we identify a rationally selected LNP formulation that reestablishes distal antigen expression across age groups as an engineering strategy to revive T cell immunity, achieving full rescue of therapeutic efficacy in aged mice without additional intervention. Together, these findings establish systemic mRNA translation as a tuneable lever of vaccine performance and highlight that optimizing LNP formulations to sustain systemic transgene expression across age groups may enable next-generation, age-adaptive mRNA vaccines for cancer and other diseases of aging.

bioengineering↗

bioRxiv2022

Cas9-Mediated Knockout of Ndrg2 Enhances the Regenerative Potential of Dendritic Cells for Wound Healing

Chronic wounds impose a significant healthcare burden to a broad patient population. Cell based therapies, while having shown benefits for the treatment of chronic wounds, have not achieved widespread adoption into clinical practice. Here, we developed a novel CRISPR/Cas9 approach to precisely edit dendritic cells (DCs) to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing (scRNA-seq) of tolerogenic DCs, we discover N-myc downregulated gene 2 (Ndrg2), which marks a specific population of DC progenitors, as a promising target for CRISPR knockout (KO). Ndrg2-KO alters the transcriptomic profile of DCs and preserves an immature cell state with a strong, pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a hydrogel technology for in vivo cell delivery and developed a highly effective translational approach for DC based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in DCs for treating various types of chronic wounds.

cell biology↗

bioRxiv2021

Xenogeneic Skin Transplantation Promotes Angiogenesis and Tissue Regeneration Through Vitamin D-Activated Trem2+ Macrophages

Skin allo- and xenotransplantation are the standard treatment for major burns when donor sites for autografts are not available and have been shown to significantly accelerate wound healing. Although the cellular elements of foreign grafts are rejected, the extracellular matrix components integrate into the wound and may underlie their beneficial effects on wound healing. The molecular mechanisms defining the relationship between the immune response to foreign grafts and their impact on wound healing have not been fully elucidated. Here, we investigated changes in collagen architecture after xenogeneic implantation of clinically available human biologic scaffolds. We show that collagen deposition in response to the implantation of human split-thickness skin grafts (hSTSG) containing live cells recapitulates normal skin architecture, whereas human acellular dermal matrix (ADM) grafts led to highly aligned collagen deposition, characteristic of fibrosis and scar. Using single-cell RNA-sequencing, we show that macrophage differentiation in response to hSTSG is driven by vitamin D (VD) signaling toward Trem2+ subpopulations with an enrichment of pro-angiogenic and anti-fibrotic transcriptomic programs. We subsequently induced this regenerative subpopulation in vitro by treating bone marrow-derived cells with vitamin D3 and found that hydrogel delivery of Trem2+ macrophages significantly accelerated wound closure in a human-like murine excisional wound model. Our study identifies the preclinical therapeutic potential of Trem2+ macrophages to mitigate fibrosis and promote wound healing and provides a novel effective strategy to develop advanced cell therapies for complex wounds. One Sentence SummaryVitamin D-activated Trem2+ macrophages promote angiogenesis and mitigate fibrosis, providing a novel effective strategy to develop advanced cell therapies for complex wounds.

immunology↗