Advanced Nanomedicines for Treating Refractory Inflammation-Related Diseases

Abstract

This review examines inflammation as a physiological defense mechanism against infectious agents, physical trauma, reactive oxygen species (ROS), and metabolic stress, which, under dysregulated conditions, may progress into chronic diseases. Nanomedicine, which integrates nanotechnology with medicine, suppresses inflammatory signaling pathways and overexpressed pro-inflammatory cytokines, such as ROS, to address inflammation-related pathologies. Current advances in nanomaterial design and synthesis strategies are systematically analyzed, with parallel discussions on toxicity mechanisms, influencing factors, and evaluation methods that are critical for clinical translation. Applications of functional nanomaterials are highlighted in the context of refractory inflammatory conditions, including wound healing, gastrointestinal disorders, and immune, neurological, or circulatory diseases, along with targeted delivery strategies. Persistent challenges in nanomedicine development, such as biocompatibility optimization, precise biodistribution control, and standardized toxicity assessment, are critically assessed. By bridging material innovation with therapeutic efficacy, this review establishes a framework for advancing nanomedicine to improve treatment outcomes while addressing translational barriers.

Keywords: Nanomedicine; Nanoparticles; Nanozymes; Pancatalysis; ROS scavenging.

Scheme 1

Schematic illustration of therapeutic nanomedicine. This includes various nanomaterials, such as NPs, liposomes, nanozymes, nanofibers, nanocrystals, micelles, and nanorods, intended for the treatment of inflammation-related diseases. Created with BioRender.com

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Schematic diagram of the design scheme for smart nanomaterials. This design strategy is primarily categorized into two approaches: stimulus-responsive and biomimetic strategies. Created with BioRender.com

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Schematic representation of computational nanomaterials. This approach involves predicting the physicochemical properties of various nanomaterial types and their interactions with living organisms using high-throughput, AI, and ML techniques. The goal is to infer the distribution, bioactivity, and toxicity of nanosystems in vivo, ultimately guiding the selection of suitable nanomaterials. Created with BioRender.com

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Schematic diagram of biosynthesis methods for nanomaterials. This process involves the synthesis of nanoscale functional materials using plant extracts and microorganisms, including fungi, bacteria, and viruses. Created with BioRender.com

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Schematic diagram of the self-assembly synthesis of nanomaterials. This process mimics the autonomous assembly behavior of biomolecules, leading to the formation of stable aggregation systems with specific structures and functions. The assembly is driven by either endogenous or exogenous forces, utilizing assembly components and biological templates. Created with BioRender.com

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Schematic diagram of toxicity problems of nanomaterials. This diagram illustrates the intrinsic mechanisms of toxicity, both direct and indirect factors, and the methods used for their accurate assessment. Created with BioRender.com

Fig. 1

a Schematic illustration depicting the fabrication of MSC-IONP and their application in the treatment of AD [204]. Copyright 2023, American Chemical Society. b Diagram illustrating the Mel-GO ND or NC complex with varying sizes and numbers of nanosheet layers. c SEM images of E. coli and S. aureus bacteria, both prior to and following treatment with Mel-GO NDs. Arrows indicate membrane lesions and collapses in the bacterial cells [206]. Copyright 2019, John Wiley and Sons

Fig. 2

a Diagrammatic representation of the fabrication process and mechanism of action of GO-PEI25k/NO-PEI1.8 k NPs. b Healing effect and antimicrobial activity of GO-PEI25k NPs, GO-PEI25k/NO NPs and GO-PEI25k/NO-PEI1.8 k NPs in MRPA-infected wound in mice [211]. Copyright 2022, American Chemical Society. c Schematic illustration of the construction, antibacterial properties, and anti-infective therapy of Pt@V₂C nanoplatforms utilizing photothermal and chemodynamic therapies [212]. Copyright 2024, John Wiley and Sons

Fig. 3

a Schematic illustration of orally administrated YMD@MPDA for targeted IBD therapy, involving ROS scavenging, anti-inflammatory, and immunomodulatory effects. b In vivo efficacy of YMD@MPDA in IBD: Quantification of colon length and histological scoring based on microscopic analysis of tissue morphology [217]. Copyright 2025, American Chemical Society. c Schematic representation of the preparation process for Q@CeBG nanoreactors and their therapeutic mechanisms in PD, focusing on neuroprotection and modulation of the brain microenvironment. d Behavioral assessment of Q@CeBG combined with FUS for the treatment of PD in mice. Representative data includes swimming speed, percent time spent in the target quadrant, and escape latency from the Morris water maze test [218]. Copyright 2024, Elsevier

Fig. 4

a Schematic illustration of PtCuO_X/CeO_2-X nanozymes for the treatment of OA. b In vivo treatment with PtCuO_X/CeO_2-X nanozymes to attenuate OA: left hind paw swing time and walking speed were measured via gait analysis after 4 and 8 weeks of treatment [220]. Copyright 2024, Springer Nature. c Schematic illustration of the synthesis of MM@Ce-CDs NPs and their role in targeted ROS-activated theranostics and regulation of the plaque microenvironment in AS. d In vivo synergistic therapeutic efficiency of MM@Ce-CDs NPs for the treatment of AS: quantitative analysis of relative lesion area of aortas, relative plaque area in cryosections from the aortic root, aortic arch, and the plaque collagen area [221]. Copyright 2025, John Wiley and Sons

Fig. 5

a Design, fabrication, and therapeutic mechanism of RBCM@CeO₂/TAK-242 [222]. Copyright 2024, John Wiley and Sons. b Schematic diagram of HPBZs for the treatment of ischemia/reperfusion injury. c In vivo efficacy of RBCM@CeO₂/TAK-242 for the treatment of ischemia/reperfusion injury: representative cerebral ¹⁸F-FDG PET images and photographs of TTC-stained coronal brain slices [223]. Copyright 2019, American Chemical Society

Fig. 6

a Catalytic disinfection mechanism proposed for the 2D bimetallic quasi-MOF_Ce0.5 nanozyme. b Plate count results showing the antibacterial effects of various nanozyme formulations against E. coli O157: H7 and S. aureus [231]. Copyright 2022, John Wiley and Sons. c Schematic illustration for the therapeutic concept of MHPH nanomedicine for catalytic anti-inflammatory treatments. d In vivo antiarthritic efficacy of MHPH: histomorphometric micro-CT analysis of fundamental parameters of bone microstructure (BV/TV, Tb.N, and Tb.Sp) [232]. Copyright 2022, American Chemical Society. e Therapeutic mechanism of ZMTP nanosheet for nanocatalytic RA treatment [233]. Copyright 2022, Springer Nature

Fig. 7

a Schematic illustration of 2D V₂C MXene-based nanozyme with intrinsic multiple enzyme-like activities as a theranostic nanoplatform for ischemic stroke treatment, alleviating oxidative stress, suppressing cell apoptosis, and counteracting inflammation. b In vivo efficacy of V₂C MXene for the treatment of ischemic stroke: representative images of TTC-stained coronal brain slides and quantitative calculation of the infarct volume [235]. Copyright 2022, Elsevier. c Schematic illustration of the fabrication process of MM@MnO₂-Au-mSiO₂@Cur and cascade-targeting anti-inflammatory therapy for TBI. d In vivo efficacy of MM@MnO₂-Au-mSiO₂@Cur for the treatment of TBI in the Morris water maze, including the time spent in the target quadrant, escape latency and the number of platform crossings [242]. Copyright 2024, John Wiley and Sons

Fig. 8

a Schematic illustration of the fabrication process and the mechanism of miR-146a-SPIONs. b In vivo efficacy of miR-146a-SPIONs for the treatment of AS: fractional plaque area in total aorta, plaque area and collagen content in aortic root [246]. Copyright 2022, National Academy of Sciences. c Schematic illustration of the fabrication of FMMON@PL and its use for the therapy of AS [247]. Copyright 2025, Elsevier. d Schematic diagram of SOD-loaded polymersomes with high membrane permeability for intra-articular joint injection. e Evaluation of therapeutic efficacy of SOD-NP for the treatment of OA: the OA severity of knee joints measured by Mankin score, Synovitis score, and von Frey assay [248]. Copyright 2022, Elsevier

Fig. 9

a Schematic illustration of the fabrication of ROS-responsive PPS-CPNs/CLT and their glomerulus-targeted delivery fate. b In vivo efficacy of PPS-CPNs/CLT for the treatment of membranous nephropathy: semiquantitative scoring of KIM-1 levels, conducted based on immunohistochemical results [250]. Copyright 2024, American Chemical Society. c Schematic design of ctLP-NPs containing a core made from PLGA and a shell made from PEG-conjugated lipid. d Therapeutic efficacy of MK-8722-loaded ctLP-NPs for repairing cartilage damage in collagenase-induced OA mice: quantification of cartilage content from safranin-O-stained sections (red) [253]. Copyright 2020, John Wiley and Sons. e Schematic diagram of ROS-responsive HTA prodrug micelles for co-delivering DEX, inhibiting the HIF-1α/NF-κB cascade to regulate ROS scavenging and macrophage repolarization in RA therapy [262]. Copyright 2022, Elsevier

Fig. 10

a Schematic illustration of biomimetic hFGF21@BCM-LIP for targeted modulation of brain inflammation via the lymphatic system for the treatment of AD. b In vivo efficacy of hFGF21@BCM-LIP for the treatment of AD in the Morris water maze, including escape latency, the number of platform crossings, swimming speed and the time spent in the target quadrant [269]. Copyright 2024, John Wiley and Sons. c Schematic illustration of the preparation and mechanisms of GelMA/DAS/Exo hydrogel [273]. Copyright 2025, Springer Nature

Scheme 7

Schematic illustration of the development and challenges of nanomedicine. This diagram encompasses the innovation of delivery routes and drug loading of nanomaterials, the exploration of mechanisms and types of nanozymes, the biosafety of nanomedicine, the clinical application of nanomaterials, and the quest for stable targeting ligands. Created with BioRender.com