Research Highlights

Biosilica Nanoparticulate Scavengers for the Therapy of Hepatic Ischemia/Reperfusion Injury in Preclinical Models Zhou B, Chen X, Ding R, et al. Nat Commun. 2025;16:7650. Ischemia/reperfusion injury (IRI) is an unavoidable consequence of organ transplantation, especially pronounced in deceased donor grafts, where prolonged ischemia contributes to cellular damage. Multiple interlinked pathways drive IRI,1 including intracellular Ca2+ overload, oxidative damage, and inflammation, compounded by microcirculation disturbances. Therapeutic strategies that target single pathways often fall short due to this complexity, making multitargeted approaches highly desirable. In their recent study, Zhou et al2 described the development of an elegant biosilica nanostructure designed to achieve such multifaceted targeting. The construct integrates 4 key components: 3 scavenger modalities for (1) cell-free DNA (cfDNA), as a source of damage-associated molecular patterns that can activate cellular inflammatory responses; (2) reactive oxygen species (ROS), as a disturbance to cell redox homeostasis and oxidative damage; (3) intracellular Ca2+, the overload of which as an inducer of activation of calcium-dependent enzymes and amplification of cellular inflammatory and oxidative responses; and (4) a modality for releasing nitric oxide, a vasodilator, from its precursor L-arginine (arg). This multifunctional nanoparticle, denoted PEI-arg@MON@BA (MNS), was synthesized stepwise by linking DNA-binding polyethylene-arginine with ROS-scavenging mesoporous organosilica nanoparticles, followed by conjugation with the calcium chelator BA. In vitro, MNS treatment effectively scavenged CaCl2, H2O2, and nucleotides, which serve as a surrogate for Ca2+, ROS, and cfDNA, likely by tightly absorbing these substances around them, while releasing nitric oxide in a controlled manner. When using sera from human recipients of liver transplant, they found that MNS treatment effectively reduced levels of cfDNA and free radicals. In macrophage and hepatocyte culture systems, they were well tolerated, readily internalized, and mitigated ROS-mediated injury and inflammation. In vivo studies in rats showed that intravenously injected MNSs passively targeted and accumulated in the liver, with much less accumulation in the spleen and lungs, and minimal accumulation in the kidney and brain. Multiple injections prolonged payload release up to 80 h. In a rat hepatic IRI model, they found that treatment significantly alleviated tissue injury both at 6 h and 24 h post-IRI, along with a reduction in the inflammatory cytokines interleukin-6, tumor necrosis factor alpha, interferon-gamma, and monocyte chemoattractant protein-1, and enhanced the expression of the anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta. Furthermore, using discarded human livers, MNS perfusion for 3 h at 4 oC significantly reduced liver ROS levels and apoptosis, and the perfusate contained less cfDNA and tumor necrosis factor alpha. Finally, using a rat liver transplant model, MNS treatment of the recipient 24 h before and 6 h after liver transplant significantly reduced ROS, necrotic lesions, and lymphocytic infiltration in the liver, along with circulating inflammatory cytokines and improved liver function indices. This work introduces a compelling proof-of-concept for bioengineered nanotherapeutics that synchronously target the multifactorial nature of IRI. The material’s stability, biocompatibility, and controlled biodegradation enhance its translational promise. Demonstration of its efficacy in clinically relevant reperfusion models (for instance, in an experimental normothermic ex vivo perfusion circuit using blood products3) would further define its potential as a versatile strategy for mitigating IRI across transplantation settings. Stem Cell–derived, Fully Differentiated Islets for Type 1 Diabetes Reichman TW, Markmann JF, Odorico J, et al. N Engl J Med. 2025;393:858–868. Current therapeutic approaches for type 1 diabetes remain constrained by several challenges, including the risk of hypoglycemia with insulin therapy, suboptimal glycemic control even with automated insulin-delivery systems, and the limited supply of donor organs for islet transplantation.1 Fully differentiated pluripotent stem cell–derived islet cells, such as zimislecel, represent a promising new frontier, offering a potentially renewable and functional source of insulin-producing tissue. In a recent multicenter trial, Reichman et al2 evaluated the safety and efficacy of zimislecel in 14 adults with type 1 diabetes and impaired hypoglycemia awareness, all of whom had undetectable fasting C-peptide levels, glycated hemoglobin (HbA1c) levels of >7%, and inadequate glycemic control despite standard insulin therapy. Zimislecel was administered via a single gravity-assisted infusion into the portal vein, accompanied by glucocorticoid-free immunosuppression. Two participants in part A of the study received a half dose (0.4 × 109 cells) with an option for a second infusion within 2 y, serving as an initial safety evaluation. Both developed detectable fasting and stimulated C-peptide by day 90, with one achieving insulin independence. One participant died of progressive neurocognitive decline unrelated to treatment. The remaining 12 participants received a full dose (0.8 × 109 cells) of zimislecel as a single infusion in part B (4 participants) and C (8 participants). In part B, infusions were given to each participant sequentially with follow-up between patients for safety, whereas in part C, all participants received infusions at the same time. One participant in part B died of cryptococcal meningitis. All 12 participants remained free from severe hypoglycemia through 1 y and achieved HbA1c levels <7% or at least a 1-percentage-point reduction from baseline at ≥1 time point between days 180 and 365, meeting the primary endpoint. For secondary endpoints, all participants reached a peak C-peptide level of at least 100 pmol/L (the threshold for a functional islet graft) during a 4-h mixed-meal tolerance test, and showed reduced postprandial glucose excursions by day 90 postinfusion. HbA1c levels dropped to <7% by day 120, and participants spent >70% of the time within the target glucose range by day 150, maintaining this control throughout the rest of the study. Exogenous insulin requirements decreased in all participants, with 10 achieving insulin independence. Most adverse events were mild or moderate, with 7 participants experiencing transient increases in liver enzymes that resolved within a month. The most common effects included diarrhea (79%), headache (71%), nausea (64%), mouth ulceration (50%), COVID-19 (50%), rash (43%), and neutropenia (43%), whereas hospitalization-requiring neutropenia and acute kidney injury occurred in 3 and 2 participants, respectively. Overall, the study reported that zimislecel can restore physiologic insulin secretion and improve glycemic control in type 1 diabetes, with detectable C-peptide, insulin independence, and the elimination of severe hypoglycemia, even in those with impaired hypoglycemia awareness, who face up to a 6-fold higher risk of severe events. These results mark a major step toward a sustainable cellular therapy for diabetes. Nevertheless, larger and longer-term studies will be essential to confirm durability, optimize immunosuppression, and assess the broader applicability of zimislecel to more diverse patient populations.