Lei Li

Heat stroke (HS) is the most severe heat-related emergency, and its pathophysiology remains largely unknown, especially for exertional HS (EHS), which affects younger populations, athletes, and manual workers. Herein, we performed single-cell-transcriptomics, T cell receptor sequencing, and flow cytometry of PBMCs from 9 healthy control participants, 9 patients with heat exhaustion, and 9 patients with EHS to explore complex immunological responses associated with HS pathobiology. We showcased that granzyme-positive T cells and CD56 ^dim NK cells with high cytotoxicity features and IL-1B ⁺ NLRP3 ⁺ monocytes with high inflammation and pyroptosis scores were enriched in HS, while the CD161 ⁺ T cells with innate immune-like, low cytotoxicity, and clonal expansion features were reduced in HS. Importantly, elevated granzyme-positive T and NK cells might interact with monocytes to induce pyroptosis of hepatic and renal cells and target organ injuries, and blocking the NLRP3 inflammasome pathway prior to the induction could alleviate organ injury in HS. This study offers deeper insights into the pathogenesis of HS, supporting the development of optimal treatment strategies.

Heat stroke (HS) is a life-threatening condition exacerbated by rising global temperatures, with children identified as a particularly vulnerable population. Despite this, basic research on age-related differences in thermotolerance remains limited. In this study, we established a high-temperature and high-humidity exposure model with real-time core body temperature (CBT) monitoring to investigate thermotolerance in young versus adult rats. The results showed that young rats exhibited prolonged CBT plateau phases and delayed HS onset, indicating enhanced thermotolerance compared to adult rats. This was accompanied by significantly milder multi-organ injury and reduced intestinal barrier damage. Young rats displayed lower serum levels of D-lactate and intestinal fatty acid-binding protein, better-preserved intestinal epithelial ultrastructure, and higher expression of tight junction proteins such as ZO-1, Occludin, and E-cadherin. Moreover, young rats showed elevated expression of heat shock proteins (HSP40 and HSP70) in intestinal tissues, which likely contributed to improved barrier integrity and cellular protection. These findings suggest that enhanced intestinal barrier stability and robust HSP responses underlie the superior thermotolerance observed in young rats. However, despite their physiological advantages, infants and young children often suffer poor HS outcomes due to behavioral limitations and caregiver negligence, especially in enclosed environments such as parked vehicles. This highlights the critical need for enhanced caregiver awareness, improved pediatric emergency response training, and preventive strategies to mitigate pediatric HS risk.

Conventional inorganic semiconductors are not suitable for acting as nanozymes or sonosensitizers for in vivo therapeutic nanomedicine owing to the lack of excellent biocompatibility. Biocompatible carbon dots (CDs) exhibit a variety of biological activities due to their adjustable size and surface chemical modification; however, the simultaneous sonodynamic activity and multiple enzyme-mimicking catalytic activity of a single CD have not been reported. Herein, we report the development of bimetallic doped CDs as a high-efficiency nanozyme and sonosensitizer for enhanced sonodynamic therapy (SDT) and nanocatalytic therapy (NCT). By selecting metal–organic complexes like EDTA–FeNa as the carbon source, we ensure that the coordination environments of metal atoms are preserved throughout the low-temperature calcination process. Compared with the single metal doped CDs including Fe–CDs or Ni–CDs, the obtained Fe and Ni co-doped CDs (Fe–Ni–CDs) not only exhibit enhanced sonodynamic activity owing to the decreased bandgap, but also possess augmented dual enzyme-mimicking catalytic activities due to the synergistic effect of bimetallic ions. The Fe–Ni–CD-mediated cascade amplification of ROS generation could lead to the production of ¹O₂ and O₂˙⁻ through SDT, the generation of ˙OH through POD-mimicking catalytic activity, and the provision of more O₂ for SDT through CAT-mimicking catalytic activity. Through the integrated multifunctionality of Fe–Ni–CDs, we successfully enhanced the effectiveness of antitumor treatment with a single drug injection and a single US irradiation for enhanced SDT and NCT. This work provides a distinct paradigm of endowing CDs with sonodynamic and multiple enzyme-mimicking catalytic activities for enhanced SDT and NCT through bimetallic ion doping.