Developing nanotherapeutics to circumvent intrinsic apoptosis resistance in cancer remains a key challenge in oncology. Cuproptosis, a non-apoptotic cell death modality, has emerged as a promising alternative, yet its therapeutic efficacy is frequently limited by robust intracellular antioxidant defense systems. Here, we developed an ultrasmall (ca.10 nm) mitochondria-targeted bimetallic nanozyme (RMOCZ) for synergistic ferroptosis-cuproptosis therapy against malignant melanoma. The Cu/Zn bimetallic core, functionalized with a chimeric mitochondrial targeting peptide, serves as both a pH-responsive copper reservoir and a dual-enzyme mimetic (peroxidase and glutathione oxidase). Upon endolysosomal acidification, RMOCZ disassembles to co-release copper ions and oridonin (ORI). The nanozyme oxidizes intracellular glutathione (GSH), a process significantly accelerated by co-delivered ORI. This disruption of redox homeostasis not only triggers ferroptosis by compromising cellular antioxidant capacity but also amplifies peroxidase-mediated reactive oxygen species (ROS) production, sensitizing tumor cells to copper-induced cytotoxicity. Concurrently, RMOCZ induces ferritinophagy to mobilize the endogenous labile iron pool and exacerbate lipid peroxidation. These events culminate in sustained copper-iron dual-ion overload. Following subsequent mitochondrial trafficking, the accumulated copper ions trigger canonical cuproptotic events, including the degradation of iron-sulfur (Fe-S) clusters and aberrant oligomerization of lipoylated DLAT. This irreversible mitochondrial dysfunction triggers potent immunogenic cell death (ICD) with robust damage-associated molecular patterns (DAMPs) release. In situ immunohistochemical analyses confirm that this RMOCZ-induced ICD profoundly remodels the immunosuppressive microenvironment, promoting CD86+ antigen-presenting cell maturation and enhancing intratumoral infiltration of CD3+ and CD8+ T cells. In vivo, RMOCZ demonstrates substantial melanoma regression with negligible systemic toxicity, providing a promising strategy for treating apoptosis-resistant refractory malignancies.

The static protection of conventional food packaging is inadequate against complex microbial and oxidative spoilage, driving the need for dynamic, responsive films. Here, we report a light-switchable, dual-functional chitosan film fabricated by supramolecular engineering of palmatine (PA) and salicylic acid (SA). The coassembly (SPA) displayed enhanced aggregation-induced emission (AIE) and generated hydroxyl radicals via type-I photodynamic process under light. Non-targeted metabolomics revealed that its photodynamic activity disrupted energy metabolism and induced oxidative stress in MRSA, causing bacterial death. Incorporated into chitosan, SPA achieved a " three birds with one stone " strategy, simultaneously enhanced the film's barrier properties, light-activated antibacterial and dark-stage antioxidant functions. Compared to CG film, CG-SPA3 film exhibited a 31.0% lower water vapor permeability. Under light, it reduced MRSA and E. coli survival to 2.39% and 5.02%, lower than 29.68% and 54.84% observed in the dark. Conversely, its antioxidant activity prevailed without light, scavenging 93.1% of center dot OH and 67.3% of ABTS center dot+. The film dynamically adapted to storage conditions, effectively preserved the nutritional quality of cherries, extended their shelf life, and also demonstrated excellent preservation efficacy for strawberries. This study provides a feasible supramolecular engineering pathway to prepare on-demand, dynamically switchable food preservation packaging.

Although the self-assembly of chiral molecules has been widely studied, the modulation of self-assembly behavior dominated by epimers that differ only in the configuration of a single chiral center remains challenging, especially since research on the biological activity of self-assemblies formed by epimers is not fully explored. Herein, we have synthesized six galloyl glycosides. Their structures differ solely in the configuration of the monosaccharide core, enabling the formation of seven pairs of epimers. Systematic investigation revealed that this stereochemical variation at the sugar scaffold dictates differences in molecular conformation, which in turn leads to distinct intensity of intermolecular hydrogen bonds and π-π stacking, such that only one compound in each pair of epimers can self-assemble to form carrier-free hydrogels. Notably, the configuration of the sugar scaffold not only modulates molecular self-assembly behavior but also exerts profound impacts on biological activity. Among the three galloyl glycosides that can self-assemble to form carrier-free hydrogels, 1,2,3,4,6-penta-O-galloyl-α-D-mannose (α-D-PGMan) demonstrates superior biocompatibility coupled with potent antibacterial efficacy. Meanwhile, it alleviates inflammation and promotes angiogenesis by regulating the phenotype of macrophages, ultimately accelerating wound healing. Therefore, this study reveals the key factors by which epimers regulate the chiral self-assembly behavior, and opens up new avenues for the development of chiral biomedical materials.

In this study, we aimed to design and synthesize a series of pentacyclic triterpenoids-triphenylphosphine (TPP) derivatives. A total of 22 derivatives were systematically synthesized and evaluated for their in vitro antibacterial activities against four pathogenic strains, namely, S. aureus, MRSA, E. coli, and P. aeruginosa, using the standard broth microdilution method. Notably, most derivatives demonstrated better antibacterial activity than the pentacyclic triterpenoids parent nucleus. Among them, Compound 1 performed the most potent antibacterial activity on MRSA (MIC = 0.78 μM), which was significantly better than norfloxacin, penicillin, tobramycin, and tetracycline at the same concentration. In addition, according to the results of hemolysis test, chick chorioallantoic membrane (CAM) assay, zebrafish toxicity test, and acute toxicity test, Compound 1 exhibited higher selectivity and biosafety. Finally, the mechanistic results suggested that Compound 1 may exert its antibacterial activity by acting on key targets such as SasG, IcaB, and MurQ, thereby affecting the biofilm formation process.

Biological function and risk coexisted in the vigorous development of nanomedicine. Its toxic accumulation risk in the human body and other health hazards also made people increasingly worried about its safety risk. In this study, the micro-morphology of multi-component self-assembly in Rhei Radix et Rhizoma (RR)-Coptidis Rhizoma (CR) were regulated by thermodynamic method to realize the difference of diarrhea effect. The nano-morphology of the decoction was transformed from fiber network (cold mixing decoction (CM)) to spherical particles (hot mix reheating decoction (HMR)) by reheating treatment. This morphological transformation was achieved by altering the arrangement of key components such as emodin (Emo) and berberine (Ber) from a staggered assembly to a face-to-face assembly, which increased the interaction area and interaction force. The fiber network in CM exhibited indiscriminate coverage, causing severe damage to intestinal probiotics. This disruption promoted tyrosine metabolism of Enterobacteriaceae, resulting in large area proliferation of pathogenic bacteria and subsequent diarrhea. In contrast, the spheroid particles of HMR selectively attached to bacteria, thereby reducing toxicity to intestinal bacteria. By promoting tryptophan metabolism, intestinal homeostasis and intestinal barrier of HMR were maintained to prevent the toxic of diarrhea. This study provides a novel strategy for the toxic study of nanomedicine and offers reference for rational use of nanomedicine in clinic.

Oral administration of insulin (INS) could be absorbed into systemic circulation only if the carrier protected it from the hostile gastrointestinal conditions. However, traditional macromolecular carriers have not totally overcome challenges in addressing these biological barriers. In this study, inspired by small molecule natural products (SMNPs), we demonstrate the multi-functional self-assembly nanoparticles (BA-Al NPs) originating from baicalin (BA) and AlCl3 through coordination bonds and hydrogen bonds. As a novel carrier for oral insulin delivery (INS@BA-Al NPs), it displayed effective capacity in pH stimuli-responsive insulin release, intestinal mucoadhesion and transepithelial absorption enhance. Meanwhile, BA improved the paracellular permeability for insulin absorption, because of its downregulation at both mRNA and protein level on internal tight junction proteins. In vivo experiments exhibited remarkable bioavailability of INS and an ideal glucose homeostasis in the type I diabetic rat model. This study offers a novel frontier of multi-functional carriers based on SMNPs with self-assembly character and bioactivity, which could be a promising strategy for diabetes therapy.

Based on supramolecular chemistry of TCM, this study investigated the interaction between Cinnamomi Cortex-Coptidis Rhizoma herb pair and compared phase states and bioactivity differences under different decoction methods(co-decoction vs individual decoction followed by mechanical mixing). Phase state variations were observed macroscopically and through turbidimetry. The herb interaction was analyzed using isothermal titration calorimetry, UV and IR spectroscopy. Particle size differences were determined by dynamic light scattering and scanning electron microscopy(SEM). Antimicrobial activity was evaluated through broth dilution, plate coating, live/dead staining, and SEM. Component analysis was conducted using UPLC-MS/MS. RESULTS:: revealed distinct supramolecular structures in Cinnamomi Cortex-Coptidis Rhizoma decoctions, with co-decoction showing more stable macroscopic phase states. The interaction was a spontaneous exothermic reaction driven by both entropy and enthalpy. UV and IR spectra revealed co-decoction demonstrated more sufficient molecular interactions, more stable supramolecular structures, and smaller particle sizes with a more centralized distribution. In addition, co-decoction resulted in higher berberine and coptisine content and stronger inhibitory activity against Staphylococcus aureus compared to mechanical mixtures. These findings indicated that co-decoction produced Cinnamomi Cortex-Coptidis Rhizoma supramolecular systems with more homogeneous phase states, enhanced measurable coptisine and berberine content, and superior antibacterial efficacy.

Scutellariae Radix-Coptidis Rhizoma herb pair is a classic traditional Chinese medicine (TCM) combination with heat-clearing, dampness-drying and detoxifying effects, extensively applied clinically against bacterial infections. Traditional water decoction and ethanol pretreatment are mainstream extraction approaches, whereas existing comparisons merely emphasize quantitative variations of bioactive compounds, neglecting the underlying supramolecular assembly differences of effective substances. Comparative analysis of solvent-induced supramolecular variations provides a novel perspective to interpret differential pharmacodynamic material bases of TCM formulas. Macroscopic and microscopic morphologies of HH-0 and HH-50 were firstly characterized by visual inspection, SEM and DLS. Their phytochemical profiles were subsequently analyzed by UHPLC-Q-Orbitrap HRMS and HPLC. Antibacterial activities against MRSA were further quantified via turbidimetry and plate assays. UV, FT-IR and MD simulations revealed divergent supramolecular assembly behaviors. Finally, untargeted metabolomics and assembly-peptidoglycan interaction simulations elucidated the underlying anti-MRSA mechanisms. The solvent pretreatment endowed HH-0 and HH-50 supramolecules with distinct characteristics. HH-50 featured rougher supramolecular surfaces and higher Zeta potential with favorable dispersibility. The two supramolecules shared consistent active constituents, and HH-50 showed elevated berberine abundance and enhanced anti-MRSA activity. Notably, HH-50 maintained superior antibacterial efficacy and interference against peptidoglycan synthesis and energy metabolism even at identical berberine doses. This confirmed that divergent supramolecular conformations determined antibacterial differences, as diminished hydrogen bonds and weakened van der Waals and electrostatic interactions enhanced the binding affinity between assemblies and MRSA. Beyond chemical composition, solvent pretreatment (water versus 50

ABSTRACT Precise regulation of small‐molecule self‐assembly remains a formidable challenge, as subtle structural variations can trigger profound reprogramming of supramolecular architectures. Herein, we demonstrate that C18‐epimerization of glycyrrhizic acid (GA) acts as a molecular switch to modulate both its self‐assembly behavior and the properties of the resulting supramolecular hydrogels. Computational simulations and experimental analyses reveal that this epimer transition induces a “domino effect” that fundamentally rewrites the self‐assembly pathway, particularly by reshaping the intermolecular hydrogen‐bonding (H‐bond) network. Isoglycyrrhizic acid (IGA), the C18‐epimer of GA, forms a densely crosslinked fiber network through a distinct tetramer stacking mode, with significantly enhanced H‐bond interactions arising from altered electrostatic surface potential and molecular planarity. These structural differences yield hydrogels with enhanced injectability and viscosity, supporting the translational potential of IGA‐based hydrogel platforms. Furthermore, IGA co‐assembled with diverse therapeutic agents to form hydrogels that improved drug dispersibility and produced enhanced therapeutic effects in the evaluated preclinical models. This study elucidates the epimer‐governed cascade from molecular stereochemistry to macroscopic function and establishes a stereochemical strategy for engineering supramolecular biomaterials.

Small interfering RNA (siRNA) hydrogels constitute an advanced therapeutic paradigm that synergizes the precision of gene silencing with engineered biomaterial carriers to overcome critical delivery barriers, including enzymatic degradation, poor cellular uptake, and systemic toxicity. This comprehensive review systematically examines: Fundamental design principles of stimuli-responsive hydrogels (thermal, reduction-sensitive, pH-triggered, and magnetic systems) enabling spatiotemporal siRNA release; Therapeutic efficacy across diverse pathologies—organ-specific tumor interventions (digestive, reproductive, respiratory systems), regenerative applications (bone/cartilage repair, spinal cord regeneration), and inflammatory diseases (arthritis, dermatitis, ocular/intestinal disorders); Translational challenges in delivery efficiency, long-term biosafety, and clinical scalability. Current research progress indicates that hydrogel-encapsulated siRNA achieves targeted modulation of pathological pathways through microenvironment-adaptive functionality, significantly enhancing local bioavailability while minimizing off-target effects. Despite promising preclinical outcomes, limitations persist in resolving biological barrier penetration, release kinetics-disease progression alignment, and carrier immunogenicity. This review underscores the transformative potential of siRNA hydrogels in redefining precision medicine and delineates critical pathways for bridging laboratory innovation to clinical practice.

Although research on small-molecule self-assembling hydrogels has made certain progress, their formation mechanism analysis is still a major challenge. Since the self-assembly process requires consideration of the optimal ratio between hydrophilic and hydrophobic groups within the molecular structure, as well as the delicate balance of intermolecular interactions, chirality, and molecular spatial arrangement in aqueous environments, the discovery of small-molecule self-assembling hydrogels ultimately often relies on serendipitous experimental findings. Here, based on the principles of molecular similarity, we systematically predicted and validated the differences in self-assembly behaviors between epimers 1,2,3,4,6-penta-O-galloyl-alpha-D-galactose (alpha-D-PGGal) and 1,2,3,4,6-penta-O-galloyl-beta-D-galactose (beta-D-PGGal) through a combined strategy of molecular dynamics (MD) simulations and density functional theory (DFT) calculations. Experimental data demonstrated that alpha-D-PGGal exhibited supramolecular hydrogel-forming capability with high consistency to theoretical prediction, whereas beta-D-PGGal failed to assemble under the identical conditions. Functional extension studies further revealed that the alpha-D-PGGal hydrogel not only displayed significant antibacterial activity but also effectively prevented chronic inflammation by regulating macrophage polarization, achieving synergistic antibacterial and antiinflammatory effects that markedly accelerated wound healing. This research not only elucidates the regulatory mechanism of epimers on self-assembly behaviors at the molecular stereoconfiguration level, but also provides a new methodological framework for the rational design of small-molecule supramolecular hydrogels.

The unique design of low molecular weight hydrogels (LMWH) without carriers has sparked great interest in biomedical applications, yet the construction of binary LMWH remains elusive due to the lack of a theoretical framework linking structure and assembly. Hence, we proposed an innovative theoretical framework, in which a subtle -OH change in parent structures triggers the interconversion of nanoparticles and nanofibers. This framework hinges on a pair of hydrophobic planar small molecules with only one -OH difference, self-assembling into binary LMWH at 1:1 ratio. Notably, LMWH featuring coptisine and chrysin exhibits superior antifungal efficacy against multidrug-resistant Candida auris compared to the clinical first-line drug fluconazole. By electrostatic adsorption, Candida auris with negative charges can specifically adhere to LMWH with positive charges, facilitating the further exertion of LMWH's pharmacological effects. This leads to the activation of the CWI-MAPK pathway, disrupting the polysaccharide components in the fungal cell wall, inhibiting cell wall biosynthesis, and exerting an antifungal effect. Subsequently, this process reduces inflammation and promotes wound healing. This carrier-free, environmentally friendly strategy has significantly enhanced our understanding of the intricate relationship between structure and assembly, and has paved the way for the theory-guided construction of binary LMWH functional biomaterials with antifungal properties.

The supramolecular chemistry of small chiral molecules has attracted widespread attention owing to their similarity to natural assembly codes. Two-component low-molecular-weight (LMW) hydrogels are crucial as they form helical structures via chirality transfer, enabling diverse functions. Herein, we report a pair of two-component chiral LMW hydrogels based on the small molecular drugs baicalin (BA), scutellarin (SCU) and berberine (BBR). The two hydrogels exhibited different helicities and abilities to adhere to methicillin-resistant staphylococcus aureus (MRSA) biofilms. The BA or SCU can each laterally interact with BBR in a tail-to-tail configuration, forming a stable hydrophobic structure, while hydrophilic glucuronide groups are exposed to a water solution to form a hydrogel. However, the tiny variant steric hindrance of the terminal OH moiety of SCU affects pi-pi stacking in the layered assembly, resulting in SCU-BBR having much stronger chirality deviation and supramolecular chirality amplification than BA-BBR. Thereafter, the OH group in SCU-BBR forms more intermolecular hydrogen bonds with MRSA biofilms, enhancing stronger adhesion and better scavenging effects than BA-BBR. This work provides a unique chiral supramolecular assembly pattern, expands the antibacterial application prospect of a two-component LMW hydrogel accompanying chirality amplification, and provides a new perspective and strategy for biofilm removal.

This study aims to explore the anti-inflammatory pharmacological components and anti-inflammatory mechanisms of the alcohol extract of Saposhnikoviae Radix (SR). The components of the alcohol extract of SR were analyzed using the UPLC-MS/MS system. The anti-inflammatory efficacy of the alcohol extract and core components of SR was evaluated using the LPS-induced inflammation model of RAW264.7 cells. The anti-inflammatory mechanism of SR in a mouse model of rheumatoid arthritis was expounded by means of serum metabolomics, network pharmacology, and molecular docking. A total of 12 chromones and 13 coumarins were identified in the alcohol extract of SR. The alcohol extract of SR and its components all had good anti-inflammatory activities. In the mouse model of rheumatoid arthritis, the glycoside compounds of SR were transformed into aglycones, thereby exerting anti-inflammatory effects. Moreover, the alcohol extract of SR alleviated the inflammatory response by up-regulating the expression levels of metabolites such as phenylalanine and tyrosine. Network pharmacology and molecular docking results show that SR could exert an anti-inflammatory effect by regulating AGE-RAGE, PI3K-Akt, TNF, MAPK, and Toll-like signaling pathways. In this study, the anti-inflammatory efficacy and mechanisms of the alcohol extract of SR are explored, with the aim of providing a reference for subsequent research.

OBJECTIVES:Staphylococcus pseudintermedius is a major pathogen of canine pyoderma, and its increasing antimicrobial resistance poses a potential threat to public health, making it crucial to explore the development of new alternative therapeutic agents. METHODS AND RESULTS:In this study, we investigated the in vitro antimicrobial activity and mechanism of inhibition of sanguinarine (SAN) against clinically resistant bacteria. In addition, a murine methicillin-resistant Staphylococcus pseudintermedius (MRSP) skin infection model was established to evaluate the therapeutic efficacy of SAN. In vitro assays revealed that the MIC and MBC of SAN against S. pseudintermedius were 39.06 μg˙mL-1 and 156.25 μg˙mL-1. SAN could delay MRSP entry into the logarithmic growth phase and disrupt the bacterial structure. Transcriptomic analysis revealed that SAN primarily impacted amino acid synthesis and metabolism. In a murine MRSP skin infection model, SAN significantly reduced bacterial load, increased serum IL-4 expression, and decreased IL-6 expression. Histopathological analysis showed reduced inflammation and improved skin structure in the SAN group, with abundant fibroblasts and macrophages. CONCLUSIONS:These results reveal that SAN can inhibit the growth of MRSP, the primary drug-resistant strain associated with canine pyoderma, and suggests SAN's potential as a therapeutic option to counteract the emergence of antimicrobial resistance.

Rheumatoid arthritis (RA) is a common chronic systemic autoimmune disease that causes cartilage and bone damage in multiple joints, ultimately leading to disability. There is an urgent need to develop multidimensional strategies to treat RA. Sinomenine (SIN) has the distinctive pharmacological activity in treating RA, but its broader clinical application is limited by its exceedingly short half-life and adverse digestive tract effects. To overcome this obstacle, a self-assembled nanohydrogel (S-G hydrogel) was designed and produced with sinomenine (SIN) and glycyrrhizic acid (GA) without carriers or catalysts through noncovalent bonding. The S-G hydrogel could promote the absorption of SIN probably by protecting SIN from releasing and degrading in the acid circumstances. Oral intake of the S-G hydrogel significantly suppressed the overactivation of neutrophil via the Nf-κb and Mapk pathways in mice with RA. Furthermore, the S-G hydrogel regulated neutrophil activity by reversing apoptosis delay and decreasing autophagy-dependent NET formation. In summary, this study presents a self-assembled hydrogel with promising potential for clinical application, and offers a novel strategy to develop new drugs from the existing patent medicine composed of compounds from traditional Chinese medicine, as well as a special insight to elucidate the herb-matching mechanism in decoction prescriptions.

OBJECTIVE: Antibiotics are the main drugs used to treat bacterial infections, which have been extensively utilized across various fields. However, the problem of antimicrobial resistance (AMR) has greatly limited its use, leading to the creation of various superbugs such as Methicillin-resistant Staphylococcus aureus (MRSA), making antibiotics less effective, become a major global public health challenge. MRSA, which is resistant to most beta-lactam and cephalosporin antibiotics, poses a significant threat to public health. Combination therapy has shown promise as a strategy to combat multi-drug-resistant bacteria. Chinese medicine also has potential applications in this field. Thus, we tried to find a new approach to overcoming MRSA by combining Chinese herb and penicillin G sodium (PGS). METHODS: The antibacterial activity of Guanghuoxiang (Herba Pogostemonis) samples was investigated by turbidimetry. Then using the checkerboard assay, live/ dead bacterial staining and scanning electron microscopy (SEM) to investigate whether the combination of Guanghuoxiang (Herba Pogostemonis) samples and PGS could improve the sensitivity of MRSA, and metabolomics was used to investigate the underlying mechanisms. RESULTS: In this study, we find that the Guanghuoxiang (Herba Pogostemonis) samples had good inhibitory effects on MRSA, and showed a synergistic effect when combined with PGS, enhancing the sensitivity of MRSA to PGS. Metabolomics data further revealed that this combination exerts a broader impact on the energy and material metabolism of the bacteria, resulting in improved antibacterial efficacy. CONCLUSION: Combining Guanghuoxiang (Herba Pogostemonis) with antibiotics could improve the sensitivity of drug-resistant bacteria, provided a new direction for solving the problem of AMR, and offered a valuable strategy for clinical response to MRSA. (c) 2025 JTCM. All rights reserved.

OBJECTIVE:Antibiotics are the main drugs used to treat bacterial infections, which have been extensively utilized across various fields. However, the problem of antimicrobial resistance (AMR) has greatly limited its use, leading to the creation of various superbugs such as Methicillin-resistant Staphylococcus aureus (MRSA), making antibiotics less effective, become a major global public health challenge. MRSA, which is resistant to most β-lactam and cephalosporin antibiotics, poses a significant threat to public health. Combination therapy has shown promise as a strategy to combat multi-drug-resistant bacteria. Chinese medicine also has potential applications in this field. Thus, we tried to find a new approach to overcoming MRSA by combining Chinese herb and penicillin G sodium (PGS). METHODS:The antibacterial activity of Guanghuoxiang (Herba Pogostemonis) samples was investigated by turbidimetry. Then using the checkerboard assay, live/ dead bacterial staining and scanning electron microscopy (SEM) to investigate whether the combination of Guanghuoxiang (Herba Pogostemonis) samples and PGS could improve the sensitivity of MRSA, and metabolomics was used to investigate the underlying mechanisms. RESULTS:In this study, we find that the Guanghuoxiang (Herba Pogostemonis) samples had good inhibitory effects on MRSA, and showed a synergistic effect when combined with PGS, enhancing the sensitivity of MRSA to PGS. Metabolomics data further revealed that this combination exerts a broader impact on the energy and material metabolism of the bacteria, resulting in improved antibacterial efficacy. CONCLUSION:Combining Guanghuoxiang (Herba Pogostemonis) with antibiotics could improve the sensitivity of drug-resistant bacteria, provided a new direction for solving the problem of AMR, and offered a valuable strategy for clinical response to MRSA.

In general, pseudoephedrine (PE) is a safe and universally employed in cold medicine, which displays powerful effect on antipyretic. Nonetheless, the sustained drug delivery system can effectively put an end to the above problems attributable to the drawbacks of low bioavailability and short intervals of administration. “Complexation” hydrogels are capturing enormous attention in a diverse array of fields in that there is no necessity to carry out external intervention for drug delivery. Nevertheless, it is prevalently acknowledged that macromolecular “complexation” hydrogels, biotin/avidin, antibodies/antigens, heterodimers, conA/glucose and cyclodextrin (CD) inclusion complexes, have several limitations of conventional drug delivery systems, such as unfavorable biological safety, undesirable intestinal wall penetrating, and extremely limited biodegradability, etc. For this reason, it is tremendously imperative to develop a natural small “complexation” hydrogel. In this context, we innovated a direct self-assembly “complexation” hydrogel (PE-GA). The PE-GA hydrogel was prepared by the incorporation of PE and glycyrrhizic acid (GA) into an aqueous dispersion without the aid of other carriers, which demonstrated dual-responsiveness including heating–cooling as well as pH. It is mainly governed by hydrogen bonds and electrostatic interactions. For cell bioavailability, there were substantial discrepancies between the PE-GA hydrogel and free PE at 72 and 84 h. For pharmacokinetic properties, there was also conspicuous discrepancy in Area Under the Curve (AUC) values between them. In subsequent antipyretic assay, PE-GA hydrogel displayed a conspicuous antipyretic effect in fever rats induced by LPS. The non-invasive fluorescence imaging was utilized to monitor the intestinal retention of the PE-GA hydrogel in mice, its unique aggregation/assembly induced retention (AIR) effect reinforced bioactive molecule retention, which may be another manifestation of enhancing antipyretic effect. Aside from that, PE-GA hydrogel played an antipyretic role by Hsp90/NF‐κB pathway. The current research revealed potential antipyretic effect of PE-GA hydrogel which could be the therapeutic option against fever.