Gliomas present a formidable challenge in oncology due to their immunosuppressive tumor microenvironment and the restricted delivery of therapeutics across the blood-brain barrier. Here, we report a novel hybrid nanoplatform (HEV) for synergistic chemo-immunotherapy, constructed by integrating honeysuckle-derived vesicle-like nanoparticles (HDVN) with paclitaxel (PTX)-loaded liposomes via PEG-mediated fusion. HDVN, extracted from Lonicera japonica Flos using sucrose gradient ultracentrifugation, measured 104 ± 2.1 nm in diameter and carried functional miRNAs, including miRNA2911, capable of modulating tumor-associated macrophage (TAM) polarization through the JNK and p38 MAPK pathway. The resulting HEV achieved an encapsulation efficiency of 86.58 ± 0.06% and were administered intranasally to exploit nasal-to-brain (N2B) delivery and enhanced permeability effects. In vitro, HEV exhibited potent cytotoxicity against C6 glioma cells (IC50: 3.93 µg/mL) and promoted M1 polarization of TAM, upregulating CD80, CD86, and MHC-II while suppressing CD206. In vivo, HEV significantly inhibited tumor growth in C6 glioma-bearing mice, extending median survival from 21 to 66 days, with reduced systemic toxicity compared to free paclitaxel. miRNA sequencing and KEGG pathway analysis confirmed the cross-kingdom immunomodulatory function of HDVN, contributing to the synergistic therapeutic effect. This study establishes HDVN and HEV as a pioneering nanoplatform for targeted chemo-immunotherapy in glioma, offering a promising strategy with potential for clinical translation.

Red blood cells have become a highly potential drug delivery platform because of their inherent biocompatibility, long-term in vivo circulation ability and excellent deformability. Controllable and instantaneous permeability of red blood cell membrane is the key strategy to achieve high-efficiency intracellular drug loading. This article comprehensively explains the structure and function of red blood cell membrane, the potential mechanism of membrane permeability and its subsequent repair, three widely used membrane permeability technologies, surface loading strategies, drug release properties and the latest clinical progress in this field. By integrating basic biological insights and technological innovations, this paper provides a valuable framework for the rational design and accelerated clinical transformation of red blood cell-mediated therapeutic systems.

Red blood cell (RBC)-based therapeutic enzyme delivery systems require cell sources that can support future standardized large-scale production, with the prerequisite that engineering modifications preserve the cells' inherent biocompatibility and long-circulating potential. In this study, we first demonstrated proof-of-principle by successfully engineering asparaginase (ASPG)-loaded erythroid cells in the human erythroid progenitor cell line (HUDEP-2), where efficient ASPG expression and intact enzymatic activity were confirmed. To facilitate clinical translation, the validated strategy was further applied to human induced pluripotent stem cells (iPSCs), and the differentiated products were systematically characterized. It is worth noting that the key membrane markers of iPSC-derived ASPG-loaded erythroid cells (i-ASPG-R), including CD47 and CD55, were comparable to those of human RBCs (hRBCs). The results of Annexin V staining indicated a healthy cell status. More importantly, these cells displayed ASPG activity equivalent to that of HUDEP-2-derived counterparts. Moreover, the expression of ASPG did not affect enucleation and the composition of globin. In vitro function assays showed that compared with the control group, the proliferation of CCRF-CEM leukemia cells was inhibited by 48% after 24 h of co-culture with i-ASPG-R. In summary, this study established an iPSC-derived platform for generating ASPG-loaded erythroid cells with favorable carrier properties and evident anti-leukemic activity in vitro, laying a conceptual foundation for future cell therapy manufacturing via optimized terminal maturation.

To develop a safe, low-cost, and efficient curcumin delivery system, emulsion gels were prepared using millet chaff prolamin (MCP) and the conjugates of MCP with gallic acid (MCP-GA) and MCP with sucralose (MCP-S). Gallic acid-binding and sucralose-glycosylation improved the emulsifying properties of MCP, increased hydrophobic interactions (from 0.43 to 0.67), crystallinity (from 27.34% to 67.58%), bound water content, and viscosity of the MCP-emulsion gel, and reduced the loss factor, thereby improving its gel structure, thermal and oxidative stability, hardness, elastically, and cohesiveness. Moreover, gallic acid-binding and sucralose-glycosylation facilitated intestinal digestion of the MCP-emulsion gel, increased curcumin encapsulation (from 84.64% to 94.33%) and loading efficiencies (from 197.35 to 241.58 μg/g), and improved curcumin's photostability, thermal stability, and bioaccessibility (from 31.33% to 76.99%). Furthermore, the MCP-GA-emulsion gel exhibited superior textural and rheological performance, highest thermal and oxidative stability, curcumin-encapsulation and loading efficiencies, and the greatest capacity to enhance curcumin stability and bioaccessibility.

The persistent evolution of SARS-CoV-2 and the concomitant risk of life-threatening hyperinflammation, such as cytokine storm syndrome, underscore the urgent need for therapeutic strategies that simultaneously target viral replication and dysregulated host immunity. Herein, we describe a dual-membrane biomimetic nanoplatform, designated [A&T]MLN, comprising siRNA-loaded lipid nanoparticles with a hybrid membrane derived from ACE2-overexpressing HEK293T cells and THP-1 macrophages. This design integrates a high-density viral decoy based on ACE2 with the inherent immunomodulatory capacity of macrophage membranes. [A&T]MLN demonstrates broad-spectrum and potent neutralization of diverse SARS-CoV-2 variants by competitively blocking viral entry, while actively scavenging key inflammatory cytokines (including IL-6, IL-1β, and TNF-α) via membrane-displayed receptors. In a murine model of acute lung injury that recapitulates COVID-19 immunopathology, [A&T]MLN treatment significantly attenuated pulmonary inflammation and tissue damage. Additionally, the platform enabled efficient cytosolic delivery of siRNA, establishing a third modality for intracellular suppression of viral gene expression. Collectively, [A&T]MLN represents a complementary triple-modal therapy that simultaneously addresses viral entry, intracellular replication, and hyperinflammation (the core interconnected pathologies of severe COVID-19), offering a versatile and adaptive strategy against evolving SARS-CoV-2 variants and related inflammatory syndromes.

Cells and their derivatives, including exosomes, are garnering heightened attention from researchers for their potential to diagnose, treat, and prevent human diseases. This interest arises from their capacity to precisely replicate complex cellular functions, thereby broadening the scope of biomedical applications. To introduce novel or enhanced functionalities, the development of innovative modification techniques is essential. Genetic engineering adeptly preserves the intrinsic properties of cells and their derivatives while concurrently enhancing and optimizing their functions. This review underscores cellular-level genetic engineering strategies and their applications in biomedical fields, highlighting the innovative techniques and their potential impact on medicine, including drug delivery and immunotherapy, with the goal of inspiring additional innovative approaches to advance biomedicine.

Natural products have attracted attention owing to their multiple antitumor effects, improved chemotherapy sensitivity, and few side effects. The combination of natural active ingredients and chemotherapy drugs could be an effective strategy for synergistic antitumor therapy by preserving their activity to inhibit the growth of tumors, while reducing the side effects of chemotherapy drugs at relatively low doses. Although the feasibility of the delivery of natural products and chemotherapy drugs has been proven, most current carriers cannot be efficiently loaded, thus leading to a discrepancy in the drug release ratio compared to the predefined loading ratio. In this study, simple nanoassemblies with controllable drug release profiles were constructed to co-deliver paclitaxel (PTX) and dihydroartemisinin (DHA) for synergistic treatment of breast cancer. The nanoassemblies demonstrated a notable capacity for loading efficiency, micro-environmental triggering of drug release, and activation of the homodimeric prodrug at the tumor site, thereby facilitating successful combination therapy. The in vitro and in vivo antitumor effects were synergistically improved by combining DHA and PTX through prodrug modifications and nanoassemblies. Our findings provide a simple and efficient strategy for the development of nanoassemblies combining natural active ingredients with chemotherapeutic drugs.

Disulfide bond (Dsb) proteins, especially DsbA, represent a promising but as-yet-unrealized target in combating multidrug-resistant (MDR) bacteria because their precise subcellular targeting through multibarrier remains a significant challenge. Here, a novel heterogenization-phase-separated nano-antibiotics (NCefoTs) is proposed, through the co-assembly of enzyme-inhibiting lipopeptides (ELp component), membrane-recognizing and disrupting lipopeptides (MLp component), and cefoperazone. The self-sorting components of MLp "concentrated island-liked clusters" on the surface of NCefoTs promote the efficient penetration of NCefoTs through the outer membrane. Triggered by the DsbA, the precisely spatiotemporal engineered NCefoTs transform to nanofibers in situ and further significantly enhance the inhibition of DsbA. The hydrolytic activity of β-lactamase and the motility function of flagella are thereby impeded, confirming the efficacy of NCefoTs in restoring susceptibility to antibiotics and inhibiting infection dissemination. By these synergistic effects of NCefoTs, the minimum inhibitory concentration of antibiotics decreases from over 300 µM to 1.56 µM for clinically isolated E. coli MDR. The survival rate of sepsis-inflicted mice is significantly enhanced from 0% to 92% upon encapsulation of cefoperazone in NCefoTs, which rapidly eliminates invading pathogens and mitigates inflammation. The universally applicable delivery system, based on an "on demands" strategy, presents a promising prospect for undruggable antibiotic targets in the periplasm to combat MDR bacteria.

This study examined the synergistic effects of combining Rhodiola rosea (RHO) and caffeine (CAF) supplementation on muscle endurance and explosiveness in SD rats and human subjects, encompassing individuals without prior exercise training experience and seasoned aerobic athletes. Male SD rats and healthy human volunteers were randomly divided into four groups: CAF, RHO, CAF + RHO, and a control group (CTR). Nutritional supplements were administered throughout the training period, and pre-and post-measurement data were collected. In both the rat model and human subjects, the RHO+CAF group demonstrated significantly greater effects compared to the use of RHO or CAF supplements individually. Rats in the RHO+CAF group demonstrated extended running and swimming times and an increase in erythropoietin (EPO) mRNA expression in comparison to the CTR. Blood parameters, such as serum EPO levels, were enhanced in the CAF + RHO group, while blood urea nitrogen (BUN) and lactate (LA) levels significantly decreased in both the RHO and CAF + RHO groups. Hepatic and muscle glycogen contents were also higher in these groups. The gene expression analysis in rats demonstrated an elevation in the mRNA levels of glucose transporter-4 (GLUT-4), peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC-1α), Monocarboxylate transporter 1 (MCT-1), and Heme Oxygenase-1 (HO-1) in both the RHO and RHO+CAF groups. For individuals without prior aerobic training experience, the RHO+CAF group showed significant improvements compared to the CTR group in maximal oxygen consumption (VO2max), 5 km run, countermovement jump (CMJ), standing long jump, and 30 m sprint. For individuals with years of aerobic training experience, the RHO+CAF group exhibited enhanced performance in the 5 km run, CMJ, and standing long jump compared to the CTR group. In conclusion, the continuous 30 days supplementation of RHO, combined with a single dose of CAF, demonstrated superior effects on muscle endurance and explosiveness in both animal and human studies when compared to the use of RHO or CAF individually.

Acute ischemic stroke (AIS) is the leading cause of disability worldwide, and recanalization therapy is significant in the hyperacute phase of AIS. However, reperfusion injury and hemorrhagic transformation after recanalization predict poor prognosis of AIS. How to minimize reperfusion injury and hemorrhagic transformation, which greatly improves the prognosis of vascular recanalization, is becoming a hot topic in AIS research and an urgent problem to be solved. A wealth of neuroprotective drug studies is now available, while some of the neuroprotectants have met with failure in human studies. It is discussed in this review about the progress in neuroprotective therapy for AIS based on understanding the pathophysiologic mechanisms of reperfusion injury and hemorrhagic transformation, as well as challenges in exploring new neuroprotectants.

Dexamethasone (Dex) is a widely used glucocorticoid in medical practice, with applications ranging from allergies and inflammation to cerebral edema and shock. Despite its therapeutic benefits, Dex is classified as a prohibited substance for athletes due to its potential performance-enhancing effects. Consequently, there is a critical need for a convenient and rapid detection platform to enable prompt and accurate testing of this drug. In this study, we propose a label-free Förster Resonance Energy Transfer (FRET) aptasensor platform for Dex detection utilizing conjugated polymers (CPs), cationic conjugated polymers (CCPs), and gene finder probes (GFs). The system operates by exploiting the electrostatic interactions between positively charged CCPs and negatively charged DNA, facilitating sensitive and specific Dex detection. The label-free FRET aptasensor platform demonstrated robust performance in detecting Dex, exhibiting high selectivity and sensitivity. The system effectively distinguished Dex from interfering molecules and achieved stable detection across a range of concentrations in a commonly used sports drink matrix. Overall, the label-free FRET Dex detection system offers a simple, cost-effective, and highly sensitive approach for detecting Dex in diverse sample matrices. Its simplicity and effectiveness make it a promising tool for anti-doping efforts and other applications requiring rapid and accurate Dex detection.

Although various types of water-oil-water (W/O/W) double emulsions were explored and applied for intestinetargeted delivery, further research was needed to protect probiotics from the gastrointestinal barrier. Thus, this study aimed to encapsulate probiotics through a gel bead-bound emulsion system to improve the ability to resist the external environment, and sustained release of probiotics. In this study, sodium caseinate (NaCas)kappa Carrageenan ( kappa Car) by Maillard reaction was prepared as the external emulsifier. Then emulsions combined with sodium alginate (SA)-carboxymethyl chitosan (CMCS) hydrogel shells to encapsulate the internal aqueous phase of L . rhamnosus 76 ( LR76 ) for intestinal targeted delivery. The gel shell assembled with SA and CMCS in a citric acid solution was demonstrated by the combination of hydrogen bonding (protonated carboxyl - COOH and - OH) and electrostatic interactions (-COO - and - NH 3 + ) through IR spectroscopy. The system also showed excellent pH responsiveness and good thermal stability. The in vitro gastrointestinal simulated experiment showed the release of probiotics was managed through their swelling behavior with survival rate reaching 90.69 +/- 0.04%. The slow-release properties of gel beads were also verified in vivo, which could be applicable in animals for further healthy effects. The 16S rRNA analysis revealed a high relative abundance of Lactobacillus from the Firmicutes, highest up to 88.08%. The above results suggested that the hydrogel bead system could be used as carriers for encapsulating probiotics, which provided a theoretical basis for the future application of probiotics in the food and pharmaceutical industries.

Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.

This study aimed to explore the impact of caffeine (CAF) encapsulated in transferrin-modified, sterically-stabilized liposomes (Tf-SSL) on the physical performance of rats, specifically forelimb grip strength, running, and swimming. The brain-targeted drug delivery system, Tf-SSL, was used for the administration of caffeine. 168 male Sprague-Dawley (SD) rats were randomly assigned to different groups, including swimming, running, running wheel, and strength groups. Each group was further subdivided into high, medium, and low dose free caffeine (HCAF, MCAF, LCAF) and Tf-SSL CAF groups, along with a control group (CON). The strength, swimming, and running groups underwent training for four weeks, three times per week. The running wheel group was placed in rearing cages for a one-week adaptation period. After the final training session, the resistance, swimming, running, and running wheel exercise capacities of the rats were tested. The rats were administered treatment via tail vein injection, while the blank CON group received 0.9 % saline solution without treatment throughout the entire process. The results demonstrated a Tf-SSL CAF group encapsulation rate of 70.58 ± 5.14 %. Increasing the concentration of supplemented caffeine led to enhanced forelimb grip strength in rats, with significant differences observed in HCAF alone group, medium-dose Tf-SSL CAF (MTf-SSL CAF), and high-dose Tf-SSL CAF (HTf-SSL CAF) groups compared to the CON group. In the running and swimming experiments, higher caffeine supplementation concentrations correlated with increased running and swimming time to exhaustion, and the MTf-SSL CAF group showed longer running and swimming time compared to the HCAF alone group. The results of rat striatal dopamine levels indicated that increased caffeine supplementation concentrations led to higher dopamine secretion, with significantly different striatal concentrations in the HCAF group, MTf-SSL CAF group, and HTf-SSL CAF group compared to the CON group. The running wheel experiment revealed that rats in the medium- and high-dose Tf-SSL CAF groups exhibited greater 6-h running distances than the HCAF group and CON group. In conclusion, caffeine supplementation improved the physical performance of rats, with the high concentration CAF group outperforming the low and medium concentration groups. Furthermore, Tf-SSL CAF demonstrated superior physical enhancement compared to caffeine supplementation alone.

Objective We sought to investigate whether the addition of nimotuzumab to gemcitabine would improve the treatment efficacy of advanced pancreatic cancer. Methods This retrospective analysis involved a total of 98 hospitalized patients harboring advanced pancreatic cancer. Depending on the specific treatment, patients were divided into study groups and control groups. The clinical efficacy, adverse reactions, and follow-up results of the 2 groups were compared, and the physical status, CA724, CA19-9, and CEA levels before and after treatment were monitored and recorded. Results After treatment, PR ratio, SD ratio, ORR, and DCR in the study group were significantly higher than those in the control group, and PD ratio was significantly lower than that in the control group (P < 0.05) the KPS score after treatment in the study group was markedly higher than that of the control group (P < 0.05). After treatment, however, significantly lower levels of the 3 indicators were observed when compared with the control group (P < 0.05). Conclusion Our study highlights a more superior combined efficacy of nimotuzumab and gemcitabine than the control regimen, exhibiting improved survival and reduced levels of CA724, CA19-9, and CEA in patients with advanced pancreatic cancer.

Recovery and survival following traumatic brain injury (TBI) depends on optimal amelioration of secondary injuries at lesion site. Delivering mitochondria-protecting drugs to neurons may revive damaged neurons at sites secondarily traumatized by TBI. Pioglitazone (PGZ) is a promising candidate for TBI treatment, limited by its low brain accumulation and poor targetability to neurons. Herein, we report a ROS-responsive nanosystem, camouflaged by hybrid membranes of platelets and engineered extracellular vesicles (EVs) (C3-EPm-|TKNPs|), that can be used for targeted delivery of PGZ for TBI therapy. Inspired by intrinsic ability of macrophages for inflammatory chemotaxis, engineered M2-like macrophage-derived EVs were constructed by fusing C3 peptide to EVs membrane integrator protein, Lamp2b, to confer them with ability to target neurons in inflamed lesions. Platelets provided hybridized EPm with capabilities to target hemorrhagic area caused by trauma via surface proteins. Consequently, C3-EPm-|PGZ-TKNPs| were orientedly delivered to neurons located in the traumatized hemisphere after intravenous administration, and triggered the release of PGZ from TKNPs via oxidative stress. The current work demonstrate that C3-EPm-|TKNPs| can effectively deliver PGZ to alleviate mitochondrial damage via mitoNEET for neuroprotection, further reversing behavioral deficits in TBI mice. Our findings provide proof-of-concept evidence of C3-EPm-|TKNPs|-derived nanodrugs as potential clinical approaches against neuroinflammation-related intracranial diseases.

Mitochondria-targeted cancer therapy is an effective method for controlling tumor growth. However, the presence of repair mechanisms in tumor cells in response to mitochondrial damage poses significant challenges for treatment. By taking advantage of intracellular self-assembly technology, a peptide nanomaterial, RC-K-FX, that enters tumor cells in a monomeric form is designed. After binding to MUC1-C inside the cell membrane, RC-K-FX assembles into a spherical structure that stably encapsulates MUC1-C, inhibiting its dimerization and blocking the repair of stress-induced mitochondrial damage in tumor cells. Moreover, the self-assembled mitochondrial toxic peptide effectively destroys the mitochondria, and the loss of mitochondrial repair significantly increases tumor cytotoxicity by disrupting the redox balance, enhancing reactive oxygen species (ROS), inhibiting the nuclear factor (NF)-κB pathway, and suppressing the epithelial-mesenchymal transition (EMT) process. After intravenous administration, RC-G-FX accumulated at the tumor site, exhibiting improved anti-tumor effects and extending the overall survival of tumor-bearing mice. Therefore, the integration of the in situ self-assembly of peptide drugs and damage to mitochondrial repair mechanisms provides effective therapeutic options for malignancy.

With the progress of modern society, obesity has gradually emerged as a major public health challenge. In recent years, there has been growing interest in the potential of caffeine (CAF) as a nutritional tool for combating obesity. While previous studies has demonstrated CAF's ability to directly influence white adipose tissue (WAT) by promoting browning and reducing obesity, the role of muscle in obesity reduction should not be overlooked. Given that exercise is a primary component of weight loss, our study aimed to investigate whether CAF can alleviate adiposity by modulating the skeletal muscle-adipose tissue crosstalk. Our study demonstrates that CAF can alleviate obesity by enhancing the expression of PGC-1 alpha through calcium-related signaling pathways in skeletal muscle, which subsequently induces the production of Irisin in myotubes and high fat diet (HFD)-fed mice in vitro. Irisin, in turn, circulates to WAT and promotes browning, thus providing a theoretical foundation for the use of CAF as a nutritional tool for weight control. Overall, our findings highlight the potential of CAF in modulating skeletal muscle-adipose tissue crosstalk and suggest that it may be an effective tool for reducing obesity.

Metal oxide nanozymes have emerged as the most efficient and promising candidates to mimic antioxidant enzymes for treatment of oxidative stress-mediated pathophysiological disorders, but the current effectiveness is unsatisfactory due to insufficient catalytic performance. Here, we report for the first time an intrinsic strain-mediated ultrathin ceria nanoantioxidant. Surface strain in ceria with variable thicknesses and coordinatively unsaturated Ce sites was investigated by theoretical calculation analysis and then was validated by preparing ∼1.2 nm ultrathin nanoplates with ∼3.0% tensile strain in plane/∼10.0% tensile strain out of plane. Compared with nanocubes, surface strain in ultrathin nanoplates could enhance the covalency of the Ce-O bond, leading to increasing superoxide dismutase (SOD)-mimetic activity by ∼2.6-fold (1533 U/mg, in close proximity to that of natural SOD) and total antioxidant activity by ∼2.5-fold. As a proof of concept, intrinsic strain-mediated ultrathin ceria nanoplates could boost antioxidation for improved ischemic stroke treatment in vivo, significantly better than edaravone, a commonly used clinical drug.

Multi-level studies have shown that Rhodiola rosea (RHO) and Caffeine (CAF) have the potential to be nutritional supplements to enhance physical performance in resistance exercise-untrained and -trained subjects. This study examined the synergistic effects of RHO (262.7 mg/kg for rats and 2.4 g for volunteers) and CAF (19.7 mg/kg for rats and 3 mg/kg for volunteers) supplementation on improving physical performance in rats, resistance exercise-untrained volunteers and resistance exercise-trained volunteers. Rats and volunteers were randomly grouped into placebo, CAF, RHO and CAF+RHO and administered accordingly with the nutrients during the training procedure, and pre- and post-measures were collected. We found that RHO+CAF was effective in improving forelimb grip strength (13.75%), erythropoietin (23.85%), dopamine (12.65%) and oxygen consumption rate (9.29%) in the rat model. Furthermore, the current results also indicated that the combination of RHO+CAF significantly increased the bench press one-repetition maximum (1RM) (16.59%), deep squat 1RM (15.75%), maximum voluntary isometric contraction (MVIC) (14.72%) and maximum repetitions of 60% 1RM bench press (22.15%) in resistance exercise-untrained volunteers. Additionally, despite the excellent base level of the resistance exercise-trained volunteers, their deep squat 1RM and MVIC increased substantially through the synergistic effect of RHO and CAF. In conclusion, combined supplementation of RHO+CAF is more beneficial in improving the resistance exercise performance for both resistance exercise-untrained and -trained volunteers. The present results provide practical evidence that the synergies of RHO and CAF could serve as potential supplementary for individuals, especially resistance exercise-trained subjects, to ameliorate their physical performances effectively and safely.