CRS 2025 Annual Meeting Conference Recap

Hot topics from the CRS 2025 Annual Meeting

Here are the hot topics discussed during the CRS 2025 sessions we followed throughout the week.

• mRNA chemistry optimization enhances its stability and translation – A plenary lecture by Drew Weissman emphasized that pseudouridine modification of mRNA improves stability, translation efficiency, and reduces immunogenicity, reminding its key role in optimizing RNA-LNP therapeutics.
• Lipid design and organization shapes LNP performance – Multiple talks highlighted how lipid composition and structure directly affect LNP function. The stereochemistry of lipids was shown to significantly influence mRNA expression, with lipid stereoisomers altering performance both in vitro and in vivo. Studies using porphyrin lipid–based LNPs demonstrated that lipid–RNA organization (modulated via N/P ratio adjustments)controls intracellular dynamics, enhancing membrane fusion and thereby improving cellular uptake and cytosolic RNA delivery. In addition, crosslinked ionizable lipids (based on imidoester crosslinkers) were demonstrated to intrinsically reprogram dendritic cell metabolism, triggering glycolysis and boosting mRNA vaccine efficacy.
• Targeted delivery is advancing rapidly – Multiple talks highlighted LNP targeting strategies, including antibody-conjugated LNPs, ligand-directed LNPs, and organ-tropic Selective Organ Targeting (SORT) LNPs, enabling precise RNA delivery to immune cells, progenitors, tumors, and specific organs — for example, T cells (e.g., CD4, CD8), hematopoietic stem cells (e.g., CD117), tumors (e.g., EGFR), inflamed brain tissue (e.g., VCAM-1), and organs such as lung, spleen, and liver. In addition, engineering the surface hydrophobicity of LNPs (e.g., dendrimer-based ionizable lipid LNPs) allows fine-tuning of organ tropism, reducing liver targeting while enhancing spleen or lung delivery.
• LNP-mediated CRISPR gene editing is expanding –LNPs are increasingly employed to deliver CRISPR components (e.g., Cas9 mRNA, sgRNAs, and donor ssDNA templates) for in vivo genome editing across multiple tissues — including lung and tumors — achieving high editing efficiencies.
• Mechanistic insights to improve design rationales –Giant Unilamellar Vesicle (GUV) models mimicking endosomal membranes are providing a deeper functional understanding of endosomal escape mechanism. Studies on lipid–RNA organization are showing how the internal arrangement of lipids and RNA within the nanoparticle influences membrane fluidity and fusion behavior, shaping how effectively LNPs enter cells and release RNA. These types of mechanistic frameworks are refining the logic behind future LNP engineering.
• Novel platforms for efficient RNA delivery – Emerging non-LNP systems, including apolipoprotein nanoparticles (aNPs) and one-component Ionizable Amphiphilic Janus Dendrimers (IAJDs), are being explored as versatile platforms for targeted and efficient RNA delivery, offering promise for future vaccine development.

Selected presentation highlights from the CRS 2025 Annual Meeting

Below, we’re sharing highlights from selected presentations by leading experts that sparked our curiosity and aligned with our work in RNA therapeutics and generation delivery innovations.

Plenary lecture: Nucleoside-modified mRNA-LNP therapeutics (Drew Weissman, Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovation)

• Incorporation of modified nucleosides (m5C, m6A, m5U, s2U, or pseudouridine) to RNA alters its immunogenic potential in dendritic cells. [1]
• Pseudouridine (Ψ) modification of mRNA diminishes its immunogenicity and improves its translational capacity and biological stability. [2], [3]
• Vaccination with nucleoside-modified mRNA-LNP formulations (m1Ψ–mRNA-LNP) elicits strong T follicular helper (Tfh) cell and germinal center (GC) B cell immune responses. Notably, robust antigen-specific Tfh responses, together with increased GC B cells and plasma cells, correlated with the generation of long-lasting, high-affinity neutralizing antibodies and sustained protective immunity. [4]
• Delivering IL-12–encoding mRNA-LNPs alongside antigen mRNA-LNPs promotes CD8+ T cell expansion, effector activity, and memory formation, enhancing protection in viral, bacterial, and tumor models. [5]
• Anti-VCAM1–LNPs delivering thrombomodulin mRNA showed selective localization to inflamed regions of the brain, suggesting that VCAM-1 targeting could provide an effective approach for treating brain pathologies. [6]
• Nucleoside-modified mRNA-loaded, CD4 antibody-conjugated LNPs enable specific and efficient delivery to CD4+ T cells in vivo, offering a powerful tool for T cell–directed immunotherapies. [7]
• CD5-targeted LNPs loaded with nucleoside-modified mRNA encoding a chimeric antigen receptor (CAR) designed against fibroblast activation protein (FAP) enables the in vivo generation of transient anti-fibrotic CAR T cells, significantly decreasing fibrosis and improving cardiac function in a mouse model of heart failure. [8]
• Capstan Therapeutics’ CPTX2309 is a targeted LNP that delivers anti-CD19 CAR mRNA to CD8+ cytotoxic T cells, promoting transient and tunable CAR T cell generation in vivo to achieve rapid and transient B cell depletion. The therapy is intended for B cell–mediated autoimmune diseases, with a Phase 1 trial under progress in healthy volunteers to assess safety, tolerability, and pharmacological profiles. [9]
• CD117-targeted LNPs delivering nucleoside-modified mRNA enable in vivo genome editing and modulation of hematopoietic stem cell (HSC) function. [10]

Therapeutic genome editing in cancer via targeted lipid nanoparticles entrapping RNAs (Dan Peer, Tel Aviv University)

• Novel ionizable lipids incorporating ethanolamine, hydrazine, and hydroxylamine linkers were developed and utilized to formulate LNPs capable of efficiently delivering nucleic acids to hard-to-transfect leukocytes. [11]
• ASSET (anchored secondary scFv enabling targeting): a recombinant, membrane-anchored lipoprotein that enables non-covalent antibody attachment to LNPs via binding to antibody crystallizable fragment (Fc) domain, ensuring consistent orientation and target-binding activity. It allows for rapid customization of cell-specific RNA delivery. This platform achieved selective in vivo targeting across multiple immune cell types and demonstrated therapeutic efficacy in inflammatory bowel disease (IBD) and lymphoma models. [12]
• CRISPR-LNP (cLNP) platform using novel amino-ionizable lipids for safe and effective delivery of Cas9 mRNA and sgRNA improved gene editing efficiency in tumors.
  • Preclinical models showed strong gene editing performance in orthotopic glioblastoma (~70% after one intracerebral dose of sgPLK1-cLNPs) and disseminated ovarian tumors (~80% after intraperitoneal administration of EGFR-targeted [using the ASSET linker system] sgPLK1-cLNPs). [13]
  • For head and neck squamous cell carcinomas (HNSCCs), EGFR-targeted (using the ASSET linker system) sgSOX2-cLNPs achieved 90% inhibition in tumor growth in a xenograft mouse model. [14]

Development of SORT LNPs for genome correction of disease-causing mutation (Daniel J. Siegwart, The University of Texas Southwestern Medical Center)

• Selective Organ Targeting (SORT) LNPs incorporate an additional, 5^th lipid component —such as DOTAP for lung, 18PA for spleen, and DODAP for liver— to alter organ tropism by reshaping the protein corona, leveraging natural plasma protein adsorption to promote receptor-mediated uptake through endocytosis.
  • Key proteins enriched in the corona of SORT LNPs include vitronectin (lung-selective LNPs), β-2-glycoprotein-1 (spleen- selective LNPs), and ApoE (liver- selective LNPs).
• Lung SORT LNPs were engineered to co-deliver CRISPR components (Cas9 mRNA, sgRNA, and donor ssDNA templates) to enable homology-directed repair-mediated CFTR gene correction in cystic fibrosis (CF) models. Following CRISPR/Cas9 editing, preclinical systems showed recovery of CFTR protein production and functional chloride transport activity. [15]

Nature-inspired nanotechnology for RNA delivery to myeloid cells and bone marrow progenitors (Roy van der Meel, Eindhoven University of Technology)

• RNA delivery platform built on natural lipoproteins, developed for selective RNA transport to circulating myeloid cells, monocyte-derived macrophages, and bone marrow HSPCs (Hematopoietic Stem and Progenitor Cells).
• The team generated apolipoprotein nanoparticle (aNP) libraries and selected lead formulations with distinct lipid compositions tailored to specific RNA cargos (siRNA, ASO, mRNA), supporting gene silencing, splice modulation, and protein expression in myeloid cells and their progenitors. [16]

References

[1]        K. Karikó, M. Buckstein, H. Ni, and D. Weissman, “Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA,” Immunity, vol. 23, no. 2, pp. 165–175, Aug. 2005, doi: 10.1016/j.immuni.2005.06.008.

[2]        K. Karikó et al., “Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability,” Molecular Therapy, vol. 16, no. 11, pp. 1833–1840, 2008, doi: 10.1038/mt.2008.200.

[3]        B. R. Anderson et al., “Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation,” Nucleic Acids Res, vol. 38, no. 17, pp. 5884–5892, May 2010, doi: 10.1093/nar/gkq347.

[4]        N. Pardi et al., “Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses,” Journal of Experimental Medicine, vol. 215, no. 6, pp. 1571–1588, Jun. 2018, doi: 10.1084/jem.20171450.

[5]        E. A. Aunins et al., “An Il12 mRNA-LNP adjuvant enhances mRNA vaccine-induced CD8 T cell responses,” 2025.

[6]        O. A. Marcos-Contreras et al., “Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier”, doi: 10.1073/pnas.1912012117/-/DCSupplemental.

[7]        I. Tombácz et al., “Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs,” Molecular Therapy, vol. 29, no. 11, pp. 3293–3304, Nov. 2021, doi: 10.1016/j.ymthe.2021.06.004.

[8]        J. G. Rurik et al., “CAR T cells produced in vivo to treat cardiac injury,” Science (1979), vol. 375, no. 6576, pp. 91–96, Jan. 2022, doi: 10.1126/science.abm0594.

[9]        “Study Details | NCT06917742 | A Study of CPTX2309 in Healthy Participants | ClinicalTrials.gov.” Accessed: Dec. 31, 2025. [Online]. Available: https://clinicaltrials.gov/study/NCT06917742?intr=CPTX2309&rank=1#study-overview

[10]     L. Breda et al., “In vivo hematopoietic stem cell modification by mRNA delivery,” Science (1979), vol. 381, no. 6656, pp. 436–443, Jul. 2023, doi: 10.1126/science.ade6967.

[11]     S. Ramishetti et al., “A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes,” Advanced Materials, vol. 32, no. 12, Mar. 2020, doi: 10.1002/adma.201906128.

[12]     R. Kedmi et al., “A modular platform for targeted RNAi therapeutics,” Nat Nanotechnol, vol. 13, no. 3, pp. 214–219, Mar. 2018, doi: 10.1038/s41565-017-0043-5.

[13]     D. Rosenblum et al., “CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy,” 2020.

[14]     R. Masarwy et al., “Targeted CRISPR/Cas9 Lipid Nanoparticles Elicits Therapeutic Genome Editing in Head and Neck Cancer,” Advanced Science, vol. 12, no. 7, Feb. 2025, doi: 10.1002/advs.202411032.

[15]     T. Wei et al., “Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models,” Nat Commun, vol. 14, no. 1, Dec. 2023, doi: 10.1038/s41467-023-42948-2.

[16]     S. R. J. Hofstraat et al., “Nature-inspired platform nanotechnology for RNA delivery to myeloid cells and their bone marrow progenitors,” Nat Nanotechnol, vol. 20, no. 4, pp. 532–542, Apr. 2025, doi: 10.1038/s41565-024-01847-3.