Turning the clock: mRNA-encoded thymic factors restore aged immunity

Signal Transduction and Targeted Therapy RESEARCH HIGHLIGHT www.nature.com/sigtrans OPEN Turning the clock: mRNA-encoded thymic factors restore aged immunity 1234567890();,: Muhammad Naveed Khan 1,2 , Hui Li3 ✉ and Xiaosong Li1,2 ✉ Signal Transduction and Targeted Therapy (2026)11:222 ; https://doi.org/10.1038/s41392-026-02706-4 In a recent study published in Nature by Friedrich et al. demonstrate that mRNA-encoded delivery of DLL1, FLT3L, and IL-7 to the liver rejuvenates aged immunity, improving vaccine responses and antitumor immunity in mice.1 This work introduces a safe, transient approach to reversing immunosenescence by reconstituting a youthful signaling niche without inducing autoimmunity as shown in Fig. 1. Ageing weakens adaptive immunity through thymic involution, diminished naïve T cell output, and accumulation of dysfunctional memory and exhausted T cell states, leading to increased susceptibility to infections, poor vaccine responses, and cancer immunotherapy failure.2 Recent studies have rigorously established that age-related thymic dysfunction is a primary driver of declining T cell immunity: enhancing thymic function through RANKL treatment or via Myc-driven thymic epithelial cell expansion restores T cell production and improves immune responses in aged mice.3,4 Previous strategies to reverse immune ageing, such as hormone therapy, cytokine administration, or heterochronic parabiosis, have been limited by toxicity, modest effects, or poor clinical feasibility. A central challenge has been how to safely and transiently restore the youthful thymic signaling milieu systemically without inducing autoimmunity or chronic inflammation.5 Friedrich et al. first mapped age-dependent immune signaling by performing single-cell and spatial transcriptomics of thymic tissue and peripheral blood T cells across the murine lifespan. They identified a pronounced decline in interactions mediated by DLL1, FLT3L, and IL-7 factors critical for T cell development, dendritic cell maintenance, and lymphocyte survival. As a result, intrathymic and circulating levels of these factors declined with age.1 In immunological homeostasis, DLL1, FLT3L, and IL-7 play different but complimentary roles. Early T cell development is hampered by the age-related reduction of DLL1, a canonical Notch ligand that guides T cell lineage commitment from hematopoietic progenitors within the thymus. Common lymphoid progenitors (CLPs) and conventional type 1 dendritic cells (cDC1s), which are crucial for antigen cross-presentation, proliferate when FLT3L acts on bone marrow progenitors.2 IL-7, a non-redundant homeostatic cytokine, supports the survival and proliferation of developing thymocytes and peripheral naïve T cells, and its reduced bioavailability with age compromises both thymic output and peripheral T cell maintenance. The coordinated decline of these three factors provided a rational basis for the combinatorial DFI intervention. To reconstitute these signals without relying on the involuted thymus,6 the authors repurposed the liver as a transient protein factory. They formulated nucleoside-modified, LNP-packaged mRNAs encoding mouse DLL1, FLT3L, and IL7 (DFI). Systemic administration led to robust hepatocyte-specific translation: DLL1 was displayed on hepatocyte surfaces, while FLT3L and IL-7 were secreted, achieving sustained but reversible systemic exposure. Importantly, this mRNA-LNP approach avoided the acute inflammatory spikes and toxicity associated with recombinant cytokine injections. mRNA-LNP has several strategic advantages over recombinant protein delivery. Due to their short half-lives, recombinant cytokines must be administered often at high doses, which frequently cause dose-limiting toxicities such as capillary leak syndrome and systemic inflammation. On the other hand, nucleoside-modified mRNAs included in liver-tropic LNPs use the natural translational machinery of hepatocytes to sustainably and physiologically create therapeutic proteins. Targeted distribution with little extrahepatic expression is made possible by the SM-102 lipid formulation’s preferential accumulation in the liver through apolipoprotein E interaction. Crucially, DLL1 cannot be supplied as a soluble protein since it is a transmembrane ligand that depends on cell-contact-dependent Notch signaling. An ectopic thymic niche is created when circulating lymphoid progenitors interact with DLL1 on hepatocyte surfaces within liver sinusoids due to hepatic expression. This spatial precision, unattainable with conventional protein therapeutics, highlights the unique versatility of mRNA-based platforms. In aged mice, repeated DFI treatment expanded bone marrow CLPs and boosted thymopoiesis, increasing recent thymic emigrants (RTEs) and restoring the peripheral naïve T cell pool without altering hematopoietic stem cell composition or myeloid bias. The treatment also expanded splenic cDC1s and reversed the accumulation of age-associated B cells. A multi-compartmental immunological rejuvenation cascade was mediated by DFI treatment. Systemically available FLT3L and IL-7 expanded the CLP pool in the bone marrow and upregulated CCR9 expression, thereby enhancing progenitor homing to the thymus. Upon arrival, circulating CLPs encountered hepatocyte-displayed DLL1 within the liver sinusoids, and potentially DLL1 presented by thymic endothelial cells, engaging Notch receptors to enforce T lineage commitment. Within the thymic microenvironment, IL-7 supported the survival and proliferation of double-negative and doublepositive thymocytes, increasing the output of RTEs that seeded peripheral lymphoid organs and replenished the naïve T cell compartment. Concurrently, FLT3L expanded splenic cDC1s, which are critical for cross-presentation to CD8⁺ T cells. Functionally, DFI preconditioning markedly enhanced antigen-specific CD8⁺ T cell 1 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 2Western Institute of Digital-Intelligent Medicine, Chongqing, China and 3Dalian Women and Children’s Medical Center, Baishan Road Reproductive Center, Dalian City, Liaoning Province, China Correspondence: Hui Li () or Xiaosong Li () Received: 15 January 2026 Revised: 10 March 2026 Accepted: 19 March 2026 © The Author(s) 2026 Turning the clock: mRNA-encoded thymic factors restore aged immunity Khan et al. 2 Fig. 1 Hepatic reconstitution of thymic trophic factors rejuvenates aged immunity. a Ageing is characterized by thymic involution, diminished production of key trophic factors (DLL1, FLT3L, IL-7), and a systemic decline in their signaling. This leads to reduced naïve T cell output, impaired cDC1 function, and an accumulation of exhausted-like T cells, resulting in poor vaccine responses and ineffective antitumor immunity. b mRNA-based hepatic reconstitution. Liver-targeted lipid nanoparticles (LNPs) deliver mRNAs encoding DLL1, FLT3L, and IL-7 (DFI) to hepatocytes. This transiently reprograms the liv (...truncated)