Nanomaterial-enabled rheumatoid arthritis treatment: An advanced investigation into photonic - acoustic - gaseous multimodal therapy

Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Current treatments mainly involve drugs and surgery, but face limitations like adverse effects, invasive complications, and poor outcomes. Emerging nanomaterial-mediated modalities, particularly photothermal therapy (PTT), photodynamic therapy (PDT), photoacoustic (PA) imaging, sonodynamic therapy (SDT), and gas therapy, have demonstrated the potential to address these limitations. PTT leverages near-infrared (NIR)-responsive nanomaterials to induce localised hyperthermia, triggering apoptosis in pathogenic synovial tissues. PDT relies on photoactivated nanophotosensitizers to precisely eliminate hyperplastic synovium through spatiotemporally controlled reactive oxygen species (ROS) production. PA imaging uses NIR light to excite nanoparticles, generating ultrasound signals that are reconstructed into images, enabling real-time monitoring and assessment of RA joints. SDT employs ultrasound-activated nanosensitizers to produce cytotoxic ROS for the targeted ablation of inflammatory cells. Complementing these approaches, gas therapy, mediated by hydrogen-releasing nanomaterials, exerts immunomodulatory effects by scavenging ROS and regulating the inflammatory microenvironment. This review examines cutting-edge nanotherapeutic strategies that integrate photonic, acoustic, and gaseous modalities for RA management. Through an analysis of innovative nanosystem designs and their therapeutic mechanisms, this review highlights the emerging paradigm of synergistic multimodality approaches, which improve efficacy while reducing systemic adverse effects. This review will provide novel perspectives for advancing next-generation multimodal precision therapies for autoimmune diseases.

Graphical abstract

1. Introduction

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterised by symmetric polyarticular inflammation, which can lead to articular cartilage and bone destruction, ultimately resulting in joint deformities and functional disability [1]. Globally, the prevalence of RA is about 0.5 %–1 %, with a marked female predominance. Onset typically occurs between 40 and 60 years of age [2]. Owing to its high disability rate and low cure rate, RA remains to pose a major public health challenge worldwide. The pathogenesis of RA is complex and centres on immune dysregulation. Abnormal activation of immune cells such as T-lymphocytes, B-lymphocytes, and macrophages, triggers excessive secretion of inflammatory mediators, particularly interleukin-6 (IL-6), IL-1β, and tumour necrosis factor-α (TNF-α). These inflammatory factors promote the abnormal proliferation and activation of synovial fibroblasts (FLS) and induce neovascularization, thereby exacerbating the pathological proliferation of synovial tissues and the formation of vascular opacities. Additionally, the persistent inflammatory microenvironment induces oxidative stress and forms a vicious cycle with local hypoxia, which promotes invasive synovial growth and leads to cartilage destruction, bone erosion, and joint deformity characteristic of RA [3,4].

Current therapeutic options for RA involves pharmacological and surgical approaches. Conventional Western drugs, used as first-line therapy, provide rapid anti-inflammatory effects but are limited by their lack of specificity, which can lead to systemic toxicity and long-term drug resistance. Traditional Chinese medicines offer multi-target immunomodulation with modest adverse-effect profiles; however, unclear mechanisms, delayed onset of action, and low bioavailability impede their standardisation. Surgery is reserved for correcting end-stage deformities: although it promptly restores joint architecture, the procedure is invasive, carries a risk of post-operative infection, and does not address persistent synovitis [4] (Fig. 1). Consequently, the development of innovative therapeutic strategies for RA remains an urgent clinical need.

Fig. 1.

Comparison of strengths and weaknesses of mainstream therapeutic approaches for RA (created by Biorender, https://biorender.com).

Recently, the use of nanomaterials in RA therapy has attracted considerable attention. Nanomaterials serve as excellent delivery vehicles and therapeutic agents owing to their unique physicochemical characteristics, such as small size, high surface area, and quantum effects [65]. These properties enable precise drug delivery, improve drug bioavailability, reduce systemic side effects, and provide significant advantages in RA treatment [66,67]. However, certain nanoparticles function solely as drug delivery vehicles, offering limited drug release within the rheumatoid arthritis microenvironment (RAM) and lacking the ability to modulate its complex physiological characteristics. Advancements in nanotechnology have led to the development of novel nanomedicines comprising photosensitizers, acoustic sensitisers, and therapeutic gases or their precursors, all of which offer the potential for multimodal synergistic therapies to address the intricate pathological microenvironment of RA [68,69].

The distinctive physicochemical attributes of novel nanomaterials have enabled emerging therapeutic modalities, including photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), gas therapy, and photoacoustic imaging (PAI), to demonstrate significant potential in modulating the pathological microenvironment of RA. In PTT, photothermal materials such as gold nanorods efficiently convert near-infrared (NIR, 700–1700 nm) light energy into heat upon irradiation. This localised temperature rise induces apoptosis through the Caspase-mediated pathway, specifically eliminating heat-sensitive, hyperplastic synovial cells. PDT relies on reactive oxygen species (ROS) generated by photosensitizers under irradiation of a specific wavelength. This process induces intense oxidative stress, leading to the collapse of mitochondrial membrane potential and DNA damage. Consequently, it selectively kills inflammatory infiltrating cells and activated synovial fibroblasts, thereby blocking the inflammatory cascade reaction [70]. SDT utilises ultrasound to activate sonosensitizer nanomaterials, enabling the in situ generation of ROS within the lesion area. This process not only directly causes oxidative damage to cell membranes and organelles but also activates the Caspase-mediated apoptotic pathway, thereby killing inflammatory cells and inhibiting synovial hyperplasia [71]. Gas therapy enables targeted and controlled release of gas molecules via nanocarriers: Oxygen (O₂) improves local hypoxia, promotes the degradation of hypoxia-inducible factor α (HIF-1α), and inhibits HIF-1α-mediated inflammation and neovascularization [72]; Hydrogen (H₂) selectively neutralizes hydroxyl-radical (⋅OH) and peroxynitrite (ONOO⁻) to alleviate oxidative stress [73]; Carbon monoxide (CO) induces the expression of heme oxygenase-1 (HO-1), negatively regulates the MAPK and NF-κB pathways, and reduces the release of TNF-α and IL-6 [74]; Hydrogen sulfide (H₂S) further synergistically improves hypoxia, activates the Nrf2-ARE antioxidant pathway, and enhances cellular defense capabilities [75]. In addition, as a key monitoring method, photoacoustic (PA) imaging utilises the photothermal expansion effect of nanoprobes to generate ultrasonic waves, enabling high-resolution, real-time, and non-invasive visualisation of synovial vascular hyperplasia and inflammatory cell infiltration. This provides accurate imaging evidence for the early diagnosis and therapeutic effect evaluation of RA [76]. These therapeutic modalities are not only highly effective, targeted, and non-invasive or minimally invasive but also reduce damage to normal tissues, providing novel ideas for RA treatment (Fig. 2).

Fig. 2.

Schematic diagram of application strategies and advantages of novel nanosystems based on photonic, acoustic, and gaseous for RA treatment.

Photonic, acoustic, and gaseous therapies have their unique advantages in RA treatment and can be combined to achieve synergistic effects. For example, PA imaging combines the high resolution of optical imaging with the deep tissue penetration of ultrasound imaging, thereby significantly enhancing the detection of inflammatory signals and the visualisation of intra-articular inflammatory lesions [77]. This advancement offers precise targeting for PTT, PDT, and SDT. In PTT, localized hyperthermia not only facilitates the controlled release of gas molecules from nanomaterial carriers under specific conditions [78] but also enhances the activation efficiency of sonosensitizers in SDT, ultimately improving anti-RA efficacy. Additionally, the ROS generated by PDT and activated by ultrasound in SDT can synergise to yield a “1 + 1 > 2” effect that can significantly improve the induction of inflammatory cell apoptosis. However, excessive ROS may cause oxidative damage to normal tissues. Gas therapy can provide the necessary antioxidants (for example, H₂) to effectively neutralise these excessive harmful ROS, thereby protecting normal tissues from damage, reducing inflammatory reactions, and augmenting reparation and regeneration of articular cartilage and synovial structures. This multimodal therapy strategy harnesses the synergistic effects of multiple mechanisms and targets, significantly improving therapeutic outcomes and reducing adverse reactions. With continued advances in nanomaterials and novel therapeutic technologies, the integration of acoustic therapy, phototherapy, and gas therapy holds great promise in RA treatment, providing patients with more precise, efficient, and safer treatment options.

This nanomaterial-based multimodal synergistic therapeutic strategy not only integrates multiple physical and chemical approaches but also generally demonstrates unique advantages compared with current cutting-edge therapies for RA, such as cell therapy, gene therapy, and traditional biological agents. Cell and gene therapies seek to correct immune dysregulation at its source but are hindered by cytokine-release syndrome, technical complexity, and prohibitive costs [79,80]. Biologics that neutralise single cytokines cannot extinguish the multifactorial RA network and carry elevated risks of infection [81]. In contrast, the nanoplatform, owing to its high degree of design flexibility, can integrate the aforementioned PTT, PDT, PAI, SDT, and gas therapy to achieve integrated diagnosis and treatment, precisely adapting to the pathological microenvironment of RA. Nanocarriers passively or actively accumulate at inflamed joints, while biodegradable materials and non-invasive activation modes minimize chronic toxicity. Although scalable manufacturing and long-term biodistribution profiles remain to be optimized, local or remotely triggered administration enhances convenience and patient adherence during lifelong therapy. In conclusion, with their integrative design and multifunctional capabilities, nanomaterial-based therapies not only overcome the constraints of mono-modal treatments but also establish complementary relationships with other strategies, collectively propelling the advancement of RA therapy toward greater precision, efficacy, and safety.

Although several reviews have catalogued nanotechnology-enabled interventions for RA, they typically spotlight individual modalities or offer material-centric overviews that neglect integrative concepts. Here, we converge the spatiotemporal precision of PTT/PDT, the deep-tissue penetration of SDT, and the immunomodulatory, anti-inflammatory, and anti-oxidative capacities of gas therapy into a unified nano-architecture that confronts the multifactorial nature of RA. Particularly, this review delves into the value of PA and fluorescence (FL) dual-mode imaging in advancing theranostic integration, highlighting the pivotal role of nano-platforms in enabling simultaneous diagnosis and treatment. By mapping the current landscape and articulating rational design principles, this review furnishes a theoretical blueprint for next-generation, precision-oriented multimodal combination regimens against RA.

2. Phototherapy

Phototherapy is a novel, non-invasive treatment method that utilises light energy to interact with biological tissues, enabling precise therapy through photothermal or photochemical reactions. PTT uses a photothermal transduction agent to convert absorbed light into localised heat, thereby inducing spatially confined thermal effects to selectively eliminate pathological lesions. In contrast, PDT utilises photosensitizers such as porphyrin derivatives that generate cytotoxic ROS under specific wavelength irradiation, enabling targeted cell elimination and immunomodulation of the RAM [82]. Both PTT and PDT offer therapeutic advantages in anti-inflammation, immunomodulation, and joint protection through heat-induced apoptosis of inflammatory cells and ROS-mediated oxidative stress, respectively, presenting new strategies for precision RA treatment (Table 1, Table 2).

Table 1.

Summary of current phototherapeutic systems for RA therapy.

Phototherapies	Nano-system	Photoresponsive agents	Targets	Animal model	Mechanisms	Effects	Key features	Limitations	Refs.
PTT	Au@CeO2-PEG	Au nanorods	–	CIA mice	1TNF-α, IL-1β, and IL-6↓ 2HIF-α↓	Significantly alleviates synovitis and cartilage damage; inhibits bone erosion, increases bone mineral density and bone volume; markedly improves joint hypoxia.	High photothermal conversion efficiency.	Potential long-term toxicity risks.	[5]
	Edu-MSCs-AuS-TA	Au nanostar	FLS	CIA mice	1TNF-α, IL-1β, and IL-6↓ 2IL-4, IL-10, and Arg-1↑ IL-22R and IL-17↓	Alleviates joint inflammation, relieves pain, promotes cartilage regeneration, inhibits bone erosion, modulates immune responses, and improves motor function.	Immune modulation synergistic effects; high photothermal conversion efficiency.	Long-term metabolism in vivo remains unknown.	[6]
	Pd@Se-HA NPs	Pd NPs	Macrophage	CIA mice	1TNF-α, IL-1β, and IL-6↓ 2IL-4, IL-10, and TGF-1β↑	Effectively suppresses inflammation and monocyte infiltration while protecting articular cartilage from erosion and degeneration.	Synergistic antioxidant and photothermal multimodal therapy.	Degradation rate and metabolic pathway not specified.	[7]
	Pd-Cys@MTX@RGD	Pd nanosheets	HUVECs	CIA mice	TNF-α and COX-2↓	Effectively suppresses inflammatory responses and pro-inflammatory cytokine expression, protects articular cartilage from erosion, while reducing MTX-induced toxicity in major organs.	Exceptional photothermal therapeutic potential; structural tunability and functionality; superior catalytic performance.	Challenges in synthetic processes; potential biosafety risks require long-term assessment.	[8]
	HA@RFM@PB@SE NPs	HPB NPs	RAFLS/Macrophage	AIA rats	1TNF-α, IL-1β, IL-6, IL-23, and IL-17↓ 2IκB-α and TIMP-1↑ p-NF-κB, MMP-1, MMP-3, and COX-2↓	Significantly suppresses synovial hyperplasia, alleviates joint swelling and deformity, mitigates bone erosion and edema, and reduces arthritis index.	Excellent biocompatibility; ROS scavenging and enzyme-mimetic activity; high drug loading capacity.	Challenges of mass production.	[9]
	FMPX NPs	HPB NPs	Macrophage and osteoclast	AIA rats	1TNF-α, IL-1β, and IL-6↓ 2P-NF-κB↓ IKB-α↑ 3RANKL, RANK, NFATc1, and TRAP↓	Exert synergistic anti-inflammatory effects, scavenge ROS, and deliver photothermal therapy to alleviate foot swelling and prevent bone damage.	Good biocompatibility; ROS scavenging capacity and enzyme-mimetic activity; low cost and relatively mild synthesis.	Challenges of mass production.	[10]
	IND@PB@M@HA	HPB NPs	Macrophage	AIA rats	1TNF-α, IL-1β, and IL-6↓ 2ROS↓	Alleviates paw erythema and edema, inhibits bone erosion and cartilage degradation, reduces inflammatory cytokine levels, and decreases joint pain-related scores in rats.	Good biocompatibility; pH-responsive drug release.	The penetrating power of light is limited.	[11]
	BPNs/Chitosan/PRP (CAP)	Black phosphorus nanosheets	–	CIA mice	1PO43− and calcium phosphate (CAP)↑ 2ROS↑	Alleviates joint swelling and inflammation in mice, reduces synovial hyperplasia, cartilage/bone destruction, and provides effective joint lubrication to minimize articular surface damage.	Joint protection and lubrication; injectability and temperature-controlled release; biodegradable with potential bone-repairing properties.	Poor stability; cost and process preparation challenges.	[12]
	BP-Rut@Gel	Black phosphorus nanosheets	–	RA rats	1TNF-α, IL-17, and IL-6↓ 2MMP-13↓	Reduces joint swelling and arthritis index scores in RA rats, suppresses serum inflammatory cytokine expression, improves histopathological joint conditions, and protects articular cartilage.	Good biocompatibility; high drug loading capacity; pH-responsive degradation; photothermal and ROS synergistic therapy; bone regeneration potential.	The preparation costs are relatively high; the stability is relatively poor.	[13]
	V-HAGC	CuS NPs	RAFLS	CIA mice	H2O2 and ‧OH↑	Reduces paw thickness, alleviates synovitis, bone erosion, and cartilage degeneration.	Efficient photothermal conversion, Fenton-like activity, and high drug loading.	Complex manufacturing process; unclear long-term metabolism.	[14]
	(CMM) hydrogel	MNP	–	CIA mice	–	Significantly reduced swelling and erythema in the inflamed areas of CIA mice.	Excellent biocompatibility; biodegradable properties; potential for PA imaging.	Limited photothermal efficiency; insufficient targeting.	[15]
	EMH-FA/TPP	MPNs	Macrophage and mitochondria	CIA mice	TNF-α, IL-1β, and IL-6↓	Targets M1 macrophages and promotes M2 polarization to alleviate joint inflammation and reverse bone erosion in RA mice.	Mitochondria-targeting; high photothermal efficiency; good biocompatibility; high drug loading.	Challenges in Process Synthesis.	[16]
PDT	SMPFs	PCPDTBT	Macrophage	AIA rats	TNF-α, IL-1β, and IL-6↓	Effectively reduces joint swelling, decreases clinical arthritis scores, and suppresses pro-inflammatory cytokine secretion.	Broadband NIR absorption; Biodegradability and biosafety; Easy surface modification for targeting.	Low photothermal conversion efficiency; Complex preparation process.	[17]
	PFHNs/TM	PCPDTBT	Macrophage	CIA mice	1TNF-α, IL-1β, and IL-6↓ IL-10↑ 2Mcl-1↓	Reduces paw thickness, alleviates joint swelling and erythema, restores normal joint architecture with smooth cartilage surfaces and well-aligned chondrocytes.	Incorporating siRNA gene therapy.	PEI toxicity concerns; siRNA stability challenges; high cost.	[18]
	TPNPs-HA	PCN-224	Macrophage	AIA rats	1TNF-α, IL-1β, and IL-6↓ IL-10↑ 2ROS↑	Reduces paw thickness and inflammatory cell infiltration in rats while decreasing serum pro-inflammatory factor expression.	Hypoxia-activated chemotherapy; highly efficient ROS generation.	Potential long-term toxicity.	[19]
	FT-HA-MTX NPs	FT NPs	Macrophage	AIA rats	1O2 and ‧OH↑ 2IL-1β and TNF-α↓	Significantly reduces joint redness and swelling, decreases pro-inflammatory cytokine levels, and improves joint structure.	Enhanced SDT via O2; synergistic SDT via Fenton-based ‧OH; high drug loading.	Long-term safety challenges	[20]
	Ce6@M-Lip	Ce6	Macrophage and mitochondria	AIA rats	TNF-α and IL-1β↓	Inhibits mitochondrial function, reduces pro-inflammatory macrophage infiltration and cytokine secretion.	Mitochondria-targeting for enhanced efficacy; low-power laser preventing exacerbated inflammation.	Low drug release efficiency; insufficient active targeting.	[21]
	700DX-liposomes	IRDye700D	Macrophage	CIA mice	–	Significantly delays the development of experimental arthritis while avoiding the side effect of systemic macrophage depletion.	Capable of FL imaging and theranostics; surface amenable to modification with proteins, peptides.	Long-term clearance and potential toxicity remain unclear; insufficient targeting.	[22]
	FA@4BC NPs	4BC	Macrophage	CIA mice	CD86, iNOS↓ CD206↑	Suppresses synovitis without cytotoxicity by sublethal-induced M1-to-M2 repolarization, with synergistic microenvironment modulation via intrinsic anti-inflammatory activity.	AIE properties for enhanced imaging contrast; good biocompatibility; inherent anti-inflammatory activity.	Activation dependent on visible laser with limited tissue penetration; potential phototoxicity.	[23]
PTT + PDT	Cu7.2S4 NPs	Cu7.2S4 NPs	–	CIA rats	1TGF-β↑ 2C-reactive protein (CRP) and TNF-α↓	Eliminates inflamed synovium with enhanced bone/cartilage preservation, reduced synovial invasion, and amplified anti-inflammatory effects; possesses antibacterial capacity to prevent joint infection.	Synergistic phototherapeutic efficacy; bone and cartilage protection; antibacterial performance; biosafety and facile synthesis.	Unknown metabolism; unclear long-term toxicity.	[24]
	VIP-HA-Au NR@CuS-MTX (V-HACM NPs)	Au NR@CuS	RAFLS	CIA mice	ROS↑	Effectively treats RA in mice by inhibiting synovial proliferation, reducing joint inflammation/edema, and alleviating cartilage damage with no systemic toxicity.	Significant synergistic effects from PTT, PDT, and chemotherapy.	Complex synthesis process; unclear long-term toxicity and metabolic pathway.	[25]
	siBiMPNH	BiMP	Macrophage/FLS	CIA rats	1NF-κB, MAPK, TNF-α, IL-1β, IL-6 and MMP-9↓ 21O2, ‧O2−↑	Effectively repairs bone erosion, alleviates synovial inflammation infiltration, immune cell penetration, and fibrosis, while modulating the synovial microenvironment.	High photothermal conversion efficiency; high specific surface area.	Potential oxidative toxicity; high cost.	[26]
	CyI&Hb/FA-LPs	CyI	Macrophage	CIA mice	1TNF-α, IL-1β, and IL-6↓ IL-10↑ 2O2 and 1O2↑ HIF-α↓ 3COX-2, IFN-γ, IL-17, VEGF, and MMP-9↓	Alleviates paw swelling and erythema, improves clinical scores, and reduces synovitis and cartilage degradation.	FL imaging capability and theranostic potential; high 1O2 quantum yield; Enhanced PDT efficacy via O2 supplementation.	Potential dark toxicity; unknown long-term toxicity and metabolic pathway.	[27]
	BSA-MTX-CyI (BMC)	CyI	SPARC	CAIA mice	1TNF-α, IL-1β, and IL-6↓ IL-10↑ 2CD206↑ iNOS↓	Promotes M1-to-M2 repolarization and apoptosis, reducing joint inflammation, bone erosion, and pro-inflammatory factors in RA mice.	Carrier-free with high drug loading; theranostic potential.	Potential dark toxicity; unknown long-term toxicity and metabolic pathway.	[28]

Table 2.

Key photothermal conversion efficiency parameters of photosensitizer-based nano-systems for PTT of RA.

Nano-system	Laser wavelength (nm)	Laser power (W/cm2)	Laser irradiation time (min)	Sample concentration	Maximum Temperature (°C)	Photothermal conversion efficiency (η)	Refs.
Au@CeO2-PEG	808	1	5	200 μg/ml	57.6	33.7 %	[5]
EDU-MSCs-AUS-TA	808	–	–	–	40	–	[6]
Pd@Se-HA	808	2.5	10	20 mg/mL	49.5	34.5 %	[7]
PD-Cys@MTX@RGD	808	0.3	10	10 mg/mL	49.7	–	[8]
HA@RFM@PB@SE	808	1	5	0.1 mg/mL	52.5	40.63 %	[9]
FA@ROM@PB@XTS	808	1	8	–	43	–	[10]
Ind@PB@M@HA	808	1	5	0.1 mg/ml	45	–	[11]
BPNs/Chitosan/PRP	808	1	8	–	45	43.19 %	[12]
BP-Rut@Gel	808	1	10	200 μg/mL	50.9	–	[13]
V-HAGC	808	0.5	10	200 μg/mL	55	45.6 %	[14]
CMM	808	0.5	3	–	52	25.9 %	[15]
EHM-FA/TPP	808	1	20	25 μg/mL	45	75.05 %	[16]
Cu7.2S4	808	1	10	500 μg/mL	55	–	[24]
V-HACM NPs	808	0.5	5	100 μg/mL	54	67.2 %	[25]
siBiMPH	808	1	10	100 μg/mL	51.1	–	[26]
CyI&Hb/FA-LPs	808	0.96	5	–	46	–	[27]
BSA-MTX-CyI	808	0.96	5	45 μg/mL	47.3	–	[28]

2.1. PTT

The core mechanism of PTT is NIR irradiation of photosensitizers to raise local temperature to 40–48 °C, suppressing pathological hyperplasia and inducing apoptosis via cytoplasmic dehydration, nucleic-acid damage, and protein denaturation [83]. Its key advantages are high specificity and minimal invasiveness: nanomaterials absorb light and convert it to heat through non-radiative relaxation, whereas normal tissues—lacking photothermal converters—are spared. Diverse nanostructures (nanorods, nanosheets, nanoshells) can be surface-functionalized with antibodies or peptides to enable receptor–ligand-mediated active targeting, enriching particles in the inflamed synovium and enhancing precise action on inflammatory cells. Challenges remain in penetration depth, material safety, and thermal control, but continuous progress in nanomaterials and targeting systems are expected to overcome these limitations. Representative photosensitizers include noble-metal nanostructures, prussian blue, black phosphorus, carbon-based materials, copper sulfide, and melanin nanoparticles. These agents show potent anti-inflammatory and joint-protective promise in RA therapy by virtue of efficient photothermal conversion and targeted delivery.

2.1.1. Noble metal nanomaterials

FDA-approved gold nanoparticles (AuNPs) demonstrate considerable promise in drug delivery, imaging, and thermal ablation. Gold nanorods (AuNRs), whose photothermal conversion efficiency and NIR absorbance can be precisely tuned, are considered optimal photothermal agents for RA. Wang et al. developed PEGylated Au@CeO₂ core–shell nanorods, where gold nanorods are encapsulated in a ceria layer (Fig. 3A). Under 808 nm laser irradiation, this system combats inflammation by eliminating synovial macrophages and reducing pro-inflammatory cytokines. The Au–CeO₂ interface enhances photothermal conversion via plasmonic effects and facilitates hot-electron transfer, promoting Ce³⁺/Ce⁴⁺ redox cycling and O₂ vacancy formation in CeO₂. This optimizes H₂O₂ decomposition, releasing O₂ to alleviate joint hypoxia. Experimentally, after 5 min of irradiation, the Au@CeO₂ suspension reached 57.6 °C and degraded 82.7 % of H₂O₂, outperforming CeO₂ alone (45.2 %). The platform synergises photothermal ablation with localized O₂ generation, enabling effective anti-arthritic action at low doses. Intra-articular delivery confines therapeutic activity to the joint, minimizing systemic toxicity. [5]. Gold nanostars (AuS) outperform AuNRs because the tip effect of their multi-branched architecture generates a stronger local electromagnetic field under NIR irradiation; together with tunable NIR absorption and a high surface-to-volume ratio, this yields superior photothermal conversion. Shin et al. loaded the glucocorticoid triamcinolone acetonide (TA) onto AuS (AuS-TA) and coupled them to MSCs subjected to inflammatory preconditioning (“educated” MSCs) (Fig. 3B). These cells overexpress chemokine receptors, enhancing their homing to inflamed joints and thereby delivering AuS-TA to sites of mild-to-moderate or severe arthritis. Under 808 nm laser irradiation, the construct elevated the local temperature by 15 °C within 5 min, evidencing efficient photothermal conversion. Notably, the study first demonstrated that PTT exerts an immunomodulatory effect in RA: laser-activated AuS-TA specifically down-regulated IL-22R on T cells, suppressed Th17 differentiation and IL-17 secretion, and interrupted the pathogenic immune axis. This finding provides a new perspective for employing PTT to modulate immune-cell function in RA. Short-term evaluations reveal no overt systemic toxicity; however, the inherent lack of biodegradability of gold nanomaterials may lead to bioaccumulation, so their long-term metabolic fate and chronic toxicity must be clarified before clinical translation [6].

Fig. 3.

Schematic diagram of noble metal and PB nanomaterials for PTT in RA treatment. (A) Near-Infrared Plasmon-Boosted Heat/Oxygen Enrichment for Reversing Rheumatoid Arthritis with Metal/Semiconductor Composites. Reprinted from Ref. [5]. Copyright 2020, American Chemical Society. (B) Inflammation-Targeting Mesenchymal Stem Cells Combined with Photothermal Treatment Attenuate Severe Joint Inflammation. Reprinted from Ref. [6]. Copyright 2023, John Wiley and Sons. (C) The cellular immunotherapy of integrated photothermal anti-oxidation Pd–Se nanoparticles in inhibition of the macrophage inflammatory response in rheumatoid arthritis. Reprinted from Ref. [7]. Copyright 2021, Elsevier. (D) Biomimetic Hybrid Membrane-Coated Xuetongsu Assisted with Laser Irradiation for Efficient Rheumatoid Arthritis Therapy. Reprinted from Ref. [9]. Copyright 2022, American Chemical Society. (E) Multifunctional Prussian blue nanoparticles loading with Xuetongsu for efficient rheumatoid arthritis therapy through targeting inflammatory macrophages and osteoclasts. Reprinted from Ref. [10]. Copyright 2025, Elsevier. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Palladium (Pd) nanostructures have recently emerged as valuable biomedical agents that combine gold-comparable photothermal conversion with catalase-like activity, enabling precise modulation of oxidative stress in RA lesions. This capability stems from the distinctive electronic configuration of palladium, which efficiently activates reactant molecules. Zheng and co-workers fabricated core–shell Pd@Se-HA nanoparticles in which a Pd core generates heat under NIR irradiation, a selenium (Se) shell scavenges ROS and up-regulates anti-inflammatory cytokines, and hyaluronic acid (HA) surface ligands confer CD44-targeting capability (Fig. 3C). The two components act synergistically to suppress macrophage-driven inflammation. Despite the shielding effect of the Se/HA outer layer, which reduces the photothermal temperature rise to 44.5 °C (versus 60.1 °C for pure Pd), the integrated nanoplatform exhibits superior therapeutic efficacy: pro-inflammatory cytokine inhibition exceeds 90 % compared with 50–60 % for Pd alone, and histopathology reveals less severe cartilage damage. Notably, the material contains 88.24 % Se; prolonged release could pose a risk of selenosis, warranting careful toxicological evaluation before clinical translation [7]. Derived from Pd NPs, "palladium blue" comprises ultra-thin hexagonal palladium nanosheets (1.8 nm thickness) that exhibit broad, intense NIR absorption. The ultra-thin architecture enables highly efficient photothermal conversion and outstanding photothermal stability. Chen et al. fabricated Pd-Cys@MTX@RGD nanosheets that home to αvβ3 integrin on inflamed vasculature via an RGD peptide, augmenting lesion accumulation while minimizing off-target thermal injury. At 10 μg/mL, the nanosheets reached 53.8 °C after 10 min of 808 nm irradiation, underscoring their exceptional photothermal capacity. In vivo imaging confirmed selective enrichment in the paws of CIA mice, leading to marked suppression of inflammation and bone erosion. Although promising, clinical translation faces two hurdles: scalable synthesis of ultra-thin nanosheets requires stringent reaction conditions, and the long-term biodistribution and systemic toxicity of metallic palladium remain to be comprehensively evaluated [8].

2.1.2. Prussian blue nanomaterials

Although noble-metal nanostructures offer superior photothermal efficacy, their uncertain long-term toxicity and high cost are key obstacles to clinical translation. Attention has therefore shifted to Prussian blue nanoparticles (PBNPs)—an FDA-approved drug which enable efficient photothermal conversion and apoptotic elimination of inflamed synovium. Specifically, PB exhibits strong NIR absorption via Fe²⁺–Fe³⁺ charge-transfer transitions, converting light to heat through non-radiative relaxation [84]. PBNPs also exhibit intrinsic catalase and superoxide dismutase activity, scavenging ROS and alleviating hypoxia to establish a dual “photothermal ablation plus catalytic modulation” mechanism [85]. Hollow PBNP structures enhance drug loading while maintaining photothermal and catalytic performance. Yu et al. developed hollow PBNPs loaded with traditional medicine ingredient SE (Fig. 3D), achieving 40.63 % photothermal conversion efficiency and targeted joint accumulation using a red-cell–synovial-fibroblast hybrid membrane (RFM) and HA. This system suppressed NF-κB signaling and MMP expression [9]. Subsequent work incorporated erythrocyte-osteoclast membrane fusion and folate-receptor targeting for improved precision (Fig. 3E) [10]. Hu et al. designed indomethacin-loaded PBNPs (IND@PB@M@HA), where NIR irradiation synergized with drug release to reduce inflammation and induce macrophage apoptosis, significantly alleviating joint swelling in AIA rats [11]. Compared to noble metals, PB offers greater surface area, lower cost, inherent MRI contrast, and biodegradable properties with 90.33 % in vivo clearance [9]. Nevertheless, targeting relies on elaborate biomimetic membrane functionalization that is hard to standardise, and batch-to-batch reproducibility remains problematic. Establishing a scalable method for PB surface engineering is therefore critical for clinical translation.

2.1.3. Black phosphorus nanomaterials

Black-phosphorus nanosheets (BPNSs) combine a puckered honeycomb lattice with high photothermal conversion and biodegradability. Strong NIR absorption affords a photothermal efficiency of 43.19 % and a temperature rise of ∼25 °C under laser irradiation, sufficient to trigger apoptosis of inflammatory cells. Degradation yields phosphate ions that participate in physiological bone metabolism, conferring osteogenic potential and high biosafety. Leveraging these properties, Pan et al. fabricated an injectable thermoresponsive hydrogel comprising BPNSs dispersed in platelet-rich-plasma-functionalized chitosan (Fig. 4A). After intra-articular injection, the formulation undergoes sol–gel transition at 37 °C, creating a physical barrier that retains therapeutics within the joint and enables sustained local release synchronised with photothermal ablation. This strategy amplifies efficacy while markedly reducing systemic toxicity [12]. Likewise, Hou et al. fabricated a BP-Rut@Gel composite hydrogel by embedding rutoside-loaded BPNs within a HA–polyvinyl alcohol 3D network (Fig. 4B). The matrix provides sustained release, modulates nanosheet liberation, and dampens rapid temperature spikes during photothermal heating, shielding adjacent healthy tissue. Under NIR irradiation, the platform exhibits robust photothermal conversion and markedly enhances transdermal drug penetration. pH-responsive release aligns closely with the acidic RA microenvironment, affording superior disease adaptability [13]. Despite these advantages, BPNs face two hurdles: high environmental sensitivity that necessitates PEGylation or encapsulation to prevent oxidation, and a complex synthetic route characterised by high cost, low yield, and poor batch-to-batch reproducibility—factors that presently impede clinical translation.

Fig. 4.

Schematic diagram of BP and other functional nanomaterials for PTT in RA treatment. (A) PRP-chitosan thermoresponsive hydrogel combined with black phosphorus nanosheets as injectable biomaterial for biotherapy and phototherapy treatment of rheumatoid arthritis. Reprinted from Ref. [12]. Copyright 2020, Elsevier. (B) The combination of hydrogels and rutin-loaded black phosphorus nanosheets treats rheumatoid arthritis. Reprinted from Ref. [13]. Copyright 2024, Elsevier. (C) A Smart Nanoreactor Based on an O₂-Economized Dual Energy Inhibition Strategy Armed with Dual Multi-stimuli-Responsive "Doorkeepers" for Enhanced CDT/PTT of Rheumatoid Arthritis. Reprinted from Ref. [14]. Copyright 2022, American Chemical Society. (D) Chemo-photothermal therapeutic effect of chitosan-gelatin hydrogels containing methotrexate and melanin on a collagen-induced arthritis mouse model. Reprinted from Ref. [15]. Copyright 2022, Elsevier. (E) Macrophage and mitochondria targeted nanoplatform to deplete and polarize M1-like macrophages for rheumatoid arthritis treatment. Reprinted from Ref. [16]. Copyright 2024, Elsevier.

2.1.4. Other functional materials

Copper sulfide (CuS) nanoparticles combine exceptional photothermal conversion with Fenton-like reactivity, making them attractive for chemodynamic/photothermal synergistic therapy. Of these architectures, hollow mesoporous CuS offers both high surface area and large pore volume, serving as an ideal drug carrier [86]. Qiu and co-workers constructed the V-HAGC smart platform from hollow mesoporous CuS (Fig. 4C); the p-type semiconductor displays broad NIR absorption and a photothermal conversion efficiency of 45.6 %. The nanoplatform co-delivers glucose oxidase (GOx) and atovaquone (ATO): GOx starves inflammatory cells by catalytically depleting glucose, whereas ATO conserves O₂ by inhibiting oxidative phosphorylation, thereby amplifying GOx activity and promoting apoptosis. In CIA mice, this metabolic intervention, coupled with photothermal ablation, produced robust therapeutic efficacy against RA [14].

Melanin, an endogenous biological macromolecule, has garnered considerable interest in biomedicine owing to its excellent biocompatibility, biodegradability, and NIR absorption. Kim et al. first applied a melanin- and methotrexate (MTX)-loaded thermosensitive hydrogel to the chemo-photothermal synergistic therapy of RA (Fig. 4D). The hydrogel exhibits a photothermal conversion efficiency of 25.9 %; after injection, it undergoes in situ gelation at body temperature, enabling local retention and controlled release of the drug within the joint. Incorporated gelatin enhances both the mechanical strength of the hydrogel and its cartilage-regeneration potential [15]. Despite these advantages, melanin's photothermal efficiency is lower than that of inorganic materials, its weak drug interactions result in limited loading and poor release control, and the low reactivity of its surface functional groups hampers chemical modification, restricting improvements in targeting and smart-release performance. Innovative materials engineering and delivery strategies are therefore urgently required to overcome these limitations.

To address the limitations of high-temperature photothermal therapy—normal-tissue damage—and the insufficient efficacy of mild hyperthermia, Guo and co-workers integrated mild photothermal stimulation with mitochondrial targeting and developed EHM-FA/TPP, a nanoplatform that dually homes to macrophages and mitochondria (Fig. 4E). This is the first report of such a strategy in RA. Hollow mesoporous silica nanospheres loaded with EGCG were coated with a Fe³⁺-tannic acid (TA)-folate (FA)/triphenylphosphine (TPP) metal–phenolic network that delivers a photothermal conversion efficiency of 75.05 %, surpassing existing materials. TPP moieties direct the nanosystem to mitochondria, where mild hyperthermia (42–45 °C) collapses mitochondrial membrane potential and selectively triggers apoptosis of M1-like macrophages. TA scavenges free radicals, while Fe³⁺—an essential trace element—follows well-defined metabolic routes, ensuring biocompatibility and immunomodulatory activity. Experiments revealed a marked reduction in arthritis score, a 42.3 % decrease in paw thickness, down-regulated pro-inflammatory cytokines, and a 68.5 % reduction in bone-erosion volume, all without evident toxicity, corroborating the high efficacy and safety of the approach [16].

Although PTT demonstrates considerable potential for RA treatment, it remains constrained by three core bottlenecks—suboptimal photothermal conversion, cellular heat resistance, and impaired lesion microcirculation. Building on insights from oncology, future efforts should explore novel agents such as amorphous nanomaterials that maximize electron-relaxation-mediated heat generation [87], and second, integrate nitric-oxide (NO)-releasing strategies that suppress heat-shock-protein expression, improve local perfusion, and relieve hypoxia [88], collectively overcoming thermal tolerance and enhancing therapeutic precision and durability.

2.2. PDT

The practice of PTT demonstrates that precise conversion of light energy into localised therapeutic effects represents an effective nanomedical strategy for RA intervention. Following this principle, PDT further expands the application dimensions of light energy. Upon irradiation with visible or NIR light, the photosensitizer transitions from the ground state to an excited state, subsequently generating ROS through two mechanisms. Type I pathway: the excited photosensitizer donates an electron to substrates (e.g., H₂O), yielding radical species such as ·OH or O₂⁻. In the dominant Type II pathway, energy is transferred to ground-state oxygen (³O₂), generating singlet oxygen (¹O₂). These ROS selectively trigger apoptosis in diseased cells and reshape the inflammatory microenvironment [89]. In RA treatment, PDT targets overproliferating FLS and infiltrating inflammatory cells, thereby inhibiting synovial proliferation and pannus formation to alleviate joint damage. Additionally, PDT ameliorates the inflammatory microenvironment in RA by orchestrating macrophage polarization toward anti-inflammatory phenotypes, downregulating pro-inflammatory cytokine cascades, and upregulating anti-inflammatory mediators. Recent advancements in nanobiotechnology have enabled the rational design of actively targeted photosensitizers and stimuli-responsive nanoplatforms, significantly enhancing RA lesion targeting and therapeutic efficacy.

2.2.1. Semiconductor polymer PCPDTBT photosensitizer

Semiconducting polymer poly [2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta [2,1-b; 3,4-b] dithiophene)-alt-4,7(2,1,3-benzothiadiazole)] (PCPDTBT) exhibits broad NIR absorption and deep tissue penetration owing to its optimal band gap and unique molecular structure, enabling concurrent photothermal and photodynamic responses. To enhance clinical utility, PCPDTBT is commonly processed into nanoparticles that improve biocompatibility, targeting, and multimodal therapeutic synergy [90]. As an organic conjugated polymer, PCPDTBT is free of heavy metals, eliminating ion-leaching toxicity, while its carbon–sulfur backbone confers high chemical stability and minimises the generation of acute toxic species in vivo, exhibiting excellent biocompatibility. Li and co-workers developed FA-receptor-targeted PCPDTBT-hybrid mesoporous silica nanosystems (SMPFs) that simultaneously produce hyperthermia and ¹O₂ under 808 nm irradiation and exploit the hypoxia-activated prodrug TPZ to potentiate macrophage killing, effectively suppressing joint inflammation (Fig. 5A) [17]. Subsequent work integrated RNA interference, creating a multifunctional platform (PFHN/TM) that synergises phototherapy, chemotherapy, and gene regulation by silencing Mcl-1 mRNA to promote macrophage apoptosis and markedly down-regulate pro-inflammatory cytokines, alleviating arthritic pathology (Fig. 5B) [18]. The efficacy of PCPDTBT platforms remains limited by intralesional hypoxia; future studies should evaluate co-delivery of anti-hypoxia agents or O₂-generating species such as manganese dioxide to overcome microenvironmental barriers and enhance therapeutic reliability.

Fig. 5.

Schematic diagram of nanomaterial design and specific mechanisms for PDT in RA treatment. (A) Folate receptor-targeting semiconducting polymer dots hybrid mesoporous silica nanoparticles against rheumatoid arthritis through synergistic photothermal therapy, photodynamic therapy, and chemotherapy. Reprinted from Ref. [17]. Copyright 2021, Elsevier. (B) A Multifunctional Nano-Delivery System Against Rheumatoid Arthritis by Combined Phototherapy, Hypoxia-Activated Chemotherapy, and RNA Interference. Reprinted from Ref. [18]. Copyright 2022, Dove Medical Press. (C) Photoresponsive metal-organic framework with combined photodynamic therapy and hypoxia-activated chemotherapy for the targeted treatment of rheumatoid arthritis. Reprinted from Ref. [19]. Copyright 2023, Elsevier. (D) A novel treatment modality for rheumatoid arthritis: Inflammation-targeted multifunctional metal-organic frameworks with synergistic phototherapy and chemotherapy. Reprinted from Ref. [20]. Copyright 2024, Elsevier. (E) A Less-is-More Strategy for Mitochondria-Targeted Photodynamic Therapy of Rheumatoid Arthritis Reprinted from Ref. [21]. Copyright 2024, John Wiley and Sons. (F) Folate-guided AIE nanoparticles integrate macrophage-targeted fluorescence imaging and photodynamic immunomodulation in rheumatoid arthritis. Reprinted from Ref. [23]. Copyright 2025, Elsevier.

2.2.2. Porphyrin-based photosensitizers

Porphyrin efficiently generates ROS via its highly conjugated structure, enabling precise photodynamic therapy [91]. However, its clinical application is limited by hydrophobic aggregation and the hypoxic microenvironment of lesions. Nano-metal–organic frameworks (MOF) overcome these limitations by integrating porphyrins as ligands within the framework, suppressing molecular aggregation and fluorescence (FL) self-quenching, while ordered arrangement boosts photoresponse and markedly increases ¹O₂ yield. Zhang et al. constructed HA-decorated porphyrin-MOF (PCN-224) nanoplatforms (TPNPs-HA) that selectively target M1 macrophages (Fig. 5C). Upon NIR irradiation, the system produces ROS for photodynamic action and consumes O₂ to activate the hypoxia-responsive prodrug TPZ, achieving synergistic chemo-photothermal therapy. At 50 μg mL⁻¹, cell viability decreased to 8.02 ± 4.56 %, underscoring potent anti-RA activity. Nevertheless, zirconium ions derived from the framework raise potential long-term biosafety concerns, and the reported 7-day toxicity evaluation is inadequate, requiring subchronic and chronic toxicity studies to establish the safety profile for prolonged use [19]. Zhao et al. engineered iron–porphyrin metal–organic framework nanoparticles (FT NPs) wherein porphyrin ligands produce ROS under 660 nm irradiation for photodynamic therapy (Fig. 5D), while the porous core loads MTX and surface HA enables macrophage targeting. Unlike conventional PDT that worsens hypoxia, FT NPs convert H₂O₂ to •OH and O₂ via Fe²⁺/Fe³⁺-mediated Fenton chemistry, mediating chemodynamic therapy while simultaneously relieving hypoxia and eliminating O₂ dependence. The platform delivers a photothermal conversion efficiency of 36.3 % and markedly reduces inflammatory cytokines in AIA rats [20]. Nevertheless, MOFs lack long-term safety data, and their potential for immune sequestration and organ accumulation necessitates the development of metabolizable frameworks and comprehensive toxicological assessment.

Conventional PDT for RA is hampered by a paradox: low irradiance yields sub-therapeutic efficacy, whereas high-intensity lasers augment cytotoxicity but aggravate inflammation. Mitochondria of pro-inflammatory cells operate under high oxidative stress and are hypersensitive to ROS, providing a rationale for targeted intervention. Zuo et al. therefore engineered mitochondria-directed liposomes (Ce6@M-Lip) in which the ALD5 peptide directs the liposomes to mitochondria. The formulation utilises the second-generation porphyrin-based photosensitizer chlorin e6 (Ce6), which exhibits strong absorption at 660–662 nm, low dark toxicity, rapid clearance, and intrinsic fluorescence, enabling integrated theranostic functionality. Relative to non-targeted controls, the mitochondrial strategy reduced the IC₅₀ against pro-inflammatory cells from 1.31 μg mL⁻¹ to 0.65 μg mL⁻¹, approximately doubling cytotoxic potency [21].

2.2.3. Other functional materials

IRDye700DX, a silicon-phthalocyanine NIR dye, produces ¹O₂ efficiently via type II photochemistry at 690 nm excitation. Leveraging this property, Dorst and co-workers encapsulated the dye into liposomes and demonstrated significant reductions in arthritis scores in CIA mice. The formulation relies on passive macrophage uptake, exhibits limited targeting, and accumulates non-specifically in the liver; moreover, the 5-day observation window is insufficient to assess long-term safety [22]. Further research has revealed that the dye's active ester enables conjugation to targeting ligands, directing it to specific cell membranes. Upon NIR irradiation, the dye undergoes conformational rearrangement, forming micropores that precipitate rapid cell death while simultaneously quenching its FL—allowing real-time treatment monitoring and charting a new course toward high-precision RA phototherapy [92].

Recently, efforts to optimise PDT for RA have focused on photosensitizers that integrate intrinsic anti-inflammatory activity with potent photodynamic effects. Curcumin, a natural polyphenol, possesses well-documented anti-inflammatory and antioxidant properties, yet its clinical translation is constrained by poor aqueous solubility and low photostability. To overcome these drawbacks, Wang and co-workers designed a curcumin derivative designated 4BC and fabricated an aggregation-induced emission (AIE)-active nanoplatform (FA@4BC NPs) that homes to macrophages via FA decoration (Fig. 5E). The molecule retains anti-inflammatory activity and, upon 480 nm irradiation, efficiently generates ¹O₂ (88.7 % of total ROS), inducing sub-lethal conversion of M1 macrophages to the M2 phenotype and activating anti-inflammatory pathways for synergistic anti-inflammatory photodynamic therapy. AIE-FL enhancement circumvents aggregation-caused quenching (ACQ) typical of conventional photosensitizers, enabling theranostic integration. Nevertheless, 4BC currently requires activation by a 480 nm visible laser with limited tissue penetration and carries the risk of ambient-light-induced phototoxicity; future investigations should incorporate NIR-II (1000–1700 nm) fluorophores to extend therapeutic depth within arthritic joints [23].

In summary, PDT nanosystems for RA treatment have evolved from conventional drug carriers into intelligent platforms that enable active targeting, pathological microenvironment responsiveness, and multimodal synergistic therapy. Their design is based on three core principles: first, surface functionalization with ligands like FA and HA enhances selective cellular uptake, while subcellular strategies such as mitochondrial targeting enable precise organelle delivery to maximize local efficacy and minimize toxicity; second, stimuli-responsive components that react to pathological cues like hypoxia and high ROS allow controlled, spatiotemporal drug release and on-demand activation; third, synergistic integration of multiple modalities including PDT, PTT, chemotherapy, gene regulation, and imaging enhances anti-inflammatory and pro-apoptotic effects for more precise and consistent outcomes. Collectively, these advances provide a translationally relevant framework to guide the future development of intelligent and efficient PDT nanosystems.

2.3. Synergistic PTT/PDT

The combination of PTT and PDT is an innovative therapeutic strategy to enhance therapeutic efficacy. PTT offers rapid action and a highly efficient thermal effect but is limited by the depth of tissue penetration of the NIR laser and the thermal tolerance of some cells. PDT has the advantages of high selectivity and minimal invasiveness; however, its efficacy is limited by the phototoxicity of the photosensitizer and the short life span of ROS. When combined, PTT can enhance the penetration of PDT photosensitizers and the efficiency of ROS generation, while PDT-generated ROS can compensate for the reduced efficacy of PTT against thermotolerant cells [93], thereby significantly improving anti-RA efficacy.

Copper-based nanoparticles offer unique advantages for RA treatment by virtue of their favourable biocompatibility, potent photothermal/photodynamic properties, and capacity to promote bone regeneration. Lu et al. first applied copper-based nanomaterials to RA therapy by developing Cu₇.₂S₄ nanoparticles (Fig. 6A). Copper vacancies within Cu₇.₂S₄ induce strong localised surface plasmon resonance in the NIR, enabling efficient light-to-heat conversion, while photo-generated holes are strongly oxidising and directly oxidise intracellular substrates to generate toxic ROS. Fenton-like chemistry further amplifies oxidative stress, synergistically mediating PTT/PDT. The nanosystem effectively ameliorates joint pathology in CIA models and exhibits antibacterial activity, yet its targeting currently depends on local injection, and its long-term metabolic fate remains undefined. Future efforts should focus on surface functionalization to enhance active targeting and on comprehensive long-term biosafety evaluation [24]. To boost performance, Huang's group engineered a AuNR@CuS yolk–shell architecture (V-HACM) surface-decorated with HA and vasoactive intestinal peptide (VIP), achieving high lesion enrichment through receptor-mediated active targeting and the EPR effect. Coupling between AuNR plasmon resonance and CuS hole vibrations intensifies photothermal output and accelerates Fenton-like reactions. Under 0.5 W cm⁻² irradiation, the nanocomposite reaches 54 °C within 5 min, outperforming either component alone, but its multistep synthesis is complex and scalable production remains challenging [25].

Fig. 6.

Schematic diagram of nanomaterial design and specific mechanisms for combination of PTT and PDT in RA treatment. (A) A New Treatment Modality for Rheumatoid Arthritis: Combined Photothermal and Photodynamic Therapy Using Cu_7.2S₄ Nanoparticles. Reprinted from Ref. [24]. Copyright 2018, John Wiley and Sons. (B) Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy. Reprinted from Ref. [26]. Copyright 2024, Elsevier. (C) Oxygen Supplementation Liposomes for Rheumatoid Arthritis Treatment via Synergistic Phototherapy and Repolarization of M1-to-M2 Macrophages. Reprinted from Ref. [27]. Copyright 2023, Elsevier. (D) Dual Targeting Biomimetic Carrier‐Free Nanosystems for Photo‐Chemotherapy of Rheumatoid Arthritis via Macrophage Apoptosis and Re‐Polarization. Reprinted from Ref. [28]. Copyright 2025, John Wiley and Sons.

Two-dimensional nanosheets are ultrathin layered materials characterized by high anisotropy and planar architectures. Among them, bismuthene nanosheets, which are composed of elemental bismuth, combine low toxicity with cost-effectiveness. Their ultrasmall thickness confers high surface reactivity and exceptional photothermal conversion efficiency, making them promising for RA therapy. Wu et al. developed an injectable pH-responsive hydrogel (siBiMPNH) incorporating bismuthene nanosheets and siRNA for RA therapy (Fig. 6B). Bismuthene nanosheets offer low toxicity and high photothermal efficiency. The hydrogel disintegrates in acidic joint environments, releasing siRNA to suppress NF-κB/MAPK signaling and bismuthene to ablate synovial cells via photothermal/photodynamic effects. This synergy attenuates inflammation, hypoxia, and hyperplasia while promoting neovascularization [26].

In addition to copper-based materials and BiNS nanomaterials, cyanine dyes—organic photosensitizers with tunable molecular structures and excellent photophysical properties—offer significant advantages for PTT of RA. Conventional Cy7, however, exhibits low photothermal efficiency and negligible ROS production. Dong et al. addressed this limitation by incorporating heavy-atom iodine into Cy7; the resulting dye (CyI) retains NIR absorbance and photothermal output while boosting ¹O₂ yield by 75 %, affording a single agent capable of PDT, PTT and imaging. FA-targeted liposomes (CyI&Hb/FA-LPs) were subsequently engineered in which haemoglobin relieves hypoxia, and FA ligands direct the nanocarriers to M1 macrophages (Fig. 6C); NIR irradiation then eradicates pathological cells and promotes their repolarization toward the anti-inflammatory M2 phenotype. Like Cy7, CyI remains strongly fluorescent, enabling imaging-guided treatment and theranostic integration. Follow-up work produced a carrier-free nanosystem (BMC) via self-assembly of bovine serum albumin with the drug, achieving high payload and SPARC-mediated inflammatory targeting while integrating synergistic chemotherapy and PTT (Fig. 6D) [[27], [28], [94]]. The long-term in vivo fate and potential toxicity of CyI as a synthetic dye remain to be systematically evaluated before clinical translation can be contemplated.

Type-II photosensitizers currently employed for RA therapy require O₂ to generate ¹O₂, thereby limiting their efficacy within the hypoxic synovium. Consequently, hypoxia-independent type-I photosensitizers that produce hydroxyl radicals via electron transfer have emerged as a promising alternative. Han and co-workers recently engineered a Cy7-derived type-I agent that, under NIR irradiation, boosts ¹O₂ yield 14.4-fold and ⋅OH output 62.1-fold. The lead compound 3ACy-3ipr induces mitophagy under hypoxic conditions, subsequently triggering ferroptosis and necroptosis, thereby providing a rationale for photodynamic strategies tailored to the hypoxic microenvironment of RA [95] (Fig. 7).

Fig. 7.

Schematic diagram of nanoparticle design and their therapeutic mechanisms for RA treatment based on photothermal and photodynamic therapy.

Despite the synergistic potential of combined PDT and PTT, clinical translation faces several critical hurdles. First, limited tissue penetration compromises efficacy: visible or NIR-I light cannot penetrate deeply into joints, leading to substantial energy loss, while increasing power risks damaging healthy tissue; future efforts should explore the NIR-II window or implantable fibre-optic systems. Second, the ultrashort half-life and nanometer-scale action radius of ROS necessitate precise co-localisation of nanocarriers with target cells, requiring intelligent delivery platforms that are efficiently internalised by diseased cells. Finally, phototoxicity poses significant safety hazards: systemically administered nanomaterials can accumulate in skin and the mononuclear phagocyte system, and ambient light exposure may trigger off-target phototoxicity. Developing nanoplatforms with high targeting specificity and rapid clearance, and accurately defining therapeutic windows, are therefore essential to ensure clinical safety.

3. Acoustic diagnosis and therapy

Owing to the intrinsic limitations of phototherapy—namely, limited penetration depth and phototoxicity—researchers are actively seeking alternative modalities for safer, more effective deep treatment of RA. Among these, ultrasound (US)-powered acoustic theranostics have emerged as highly promising. Unlike light, US penetrates tissue readily and can non-invasively reach and focus on inflamed synovium within deep joints such as the knee with minimal attenuation, enabling precise energy delivery to deep-seated lesions. This capability not only circumvents the penetration bottleneck of optical methods but also eliminates ionising radiation and phototoxicity risks associated with conventional phototherapy. Building on these advantages, integrated platforms that combine high-resolution, high-contrast PA imaging with SDT are emerging as a compelling RA theranostic strategy [96] (Table 3).

Table 3.

Summary of current acoustic systems for RA diagnosis and therapy.

Acoustic diagnosis and therapy	Nano-system	Generation NPs	Targets	Animal model	Mechanisms	Effects	Key features	Limitations	Refs.
PA	IL4@AuNCs	Au NCs	Macrophage	AIA mice	1TNF-α, IL-1β, and IL-6↓ 2iNOS↓ Arg-1↑ 3Sox-9, Col-2, and Aggrecan↑ MMP-9↓	Regulates the inflammatory microenvironment, promotes macrophage M2 polarization, and reduces inflammatory factor secretion.	High optical absorption and signal enhancement; multimodal imaging compatibility.	Potential long-term clearance issues.	[29]
	M@P-siRNAsT/I	PBNPs	Macrophage	CIA mice	1TNF-α, IL-6, MMP3, MMP13, and VEGF↓ 2O2↑ HIF-α and ROS↓	Improves joint erosion, hypoxia inhibition, and anti-inflammation.	Excellent photostability; enzyme-like activity; good biosafety.	Metabolic pathway requires further clarification; high cost.	[30]
	GF-TF	MPNs	Macrophage	CIA mice	TNF-α, IL-1β, and IL-6↓	Significantly inhibits inflammatory synovitis, protects joint cartilage, prevents bone erosion, and reduces inflammatory cytokine secretion.	Real-time monitoring of drug release; structure-responsive signal changes; MRI imaging capability.	Limited signal stability.	[31]
	MNP-PEG-RGD	MNPs	Vascular endothelial cell	AIA mice	–	The PA signals produced by nanoparticles allow for real-time assessment of therapeutic response in RA.	Good biocompatibility; high optical stability.	Potential non-specific uptake.	[32]
	M-TDNPs	TT-BTA	Macrophage	CIA mice	1TNF-α, IL-1β, and IL-6↓ 2NO↓	Allows real-time RA monitoring and grading while mitigating inflammation, cartilage damage, and promoting bone repair.	NO-responsive "turn-on" signal; efficient PA conversion; good biocompatibility and stability.	Complex synthesis; difficult scale-up production.	[33]
	TCZ-PNPs	PBDTBBT	–	CIA mice	–	Alleviates forepaw inflammation in CIA mice, reduces synovial hyperplasia, immune cell infiltration, and bone destruction, while enabling adjunctive NIR-II PMI for RA therapeutic monitoring.	First example of NIR-II PMI for RA theranostics; intense NIR-II absorption and high photostability; High penetration depth and SNR; good biosafety.	Complex synthesis and high cost.	[34]
PA/FL	FA-CF-NP	Cptnc-4F (CF)	Macrophage	CIA mice	–	Specifically targets macrophages for monitoring early-stage macrophage alterations and diagnosing RA progression.	Early diagnostic capability; low background interference; higher sensitivity.	Lacks disease responsiveness; monitoring-only function without therapeutic effect.	[35]
	GAC	Cypate	Neutrophils	CIA mice	TNF-α, IL-1β, and IL-6↓ IL-10↑	Guides RA photothermal therapy while dynamically monitoring inflammatory recruitment, downregulating pro-inflammatory cytokines in serum.	Dual NIR peaks 725 nm and 800 nm) enabling flexible excitation wavelength choice.	Limited stability; prone to photodegradation and aggregation-caused FL quenching.	[36]
	TPC-U@HAT	TPY	Macrophage	ZIA mice + CIA mice	1TNF-α, IL-1β, and IL-6↓ 2NLRP3, NF-κB p65, and pSTAT1↓	Alleviates joint inflammation, attenuates MSOT/FL signals, suppresses paw swelling, reduces articular cartilage erosion, and improves motor function in mice.	Specific activation with low background and high SNR; enhanced sensitivity; MSOT imaging enabling signal source resolution beyond detection.	Probe stability limitations; high equipment cost.	[37]
	FPA	FPA	–	–	–	With mitochondrial targeting and passive accumulation, the FPA probe enables spatiotemporal HNO imaging in arthritic mice upon local injection.	First probe developed for in vivo HNO-activated imaging of inflammatory diseases.	Unknown long-term biodistribution, clearance, and chronic toxicity.	[38]
SDT	IGG	IGG	MH7A	–	ROS↑	Significantly reduces mitochondrial membrane potential, markedly increases ROS generation, and induces apoptosis in MH7A cells.	First use of SDT in anti-arthritis research.	Poor photostability; non-specific distribution.	[39]
	Bi NTs-ZnPP/HSA	ZnPP	SPARC	CIA mice	1TNF-α, IL-1β, and IL-6↓ 2O2↑ HIF-α, VEGF, and MMP-3↓ 3ROS and Bax↑ Bcl-2↓	Alleviates bone erosion, joint swelling, and synovitis while reducing hypoxia response and pro-inflammatory cytokine expression, promoting apoptosis over necrosis.	HO-1 inhibition for enhanced SDT efficacy; high drug loading capacity; good biocompatibility.	Challenging scale-up preparation.	[40]
	Fe3O4-PPIX@Mφs	PPIX	Macrophage	CIA mice	1TNF-α, IL-1β, and IL-6↓ 2ROS and ‧OH↑	Significantly reduces joint swelling, ameliorates synovial hyperplasia, cartilage damage, and inflammatory cell infiltration, while decreasing pro-inflammatory cytokine levels in serum.	Catalyzes ·OH generation from H2O2 via Fenton reaction, synergistic with SDT; good biocompatibility; FL imaging capability.	Limited photostability.	[41]
	Rh/SPX-HSA	SPX	RAFLS	CIA mice	1TNF-α, IL-1β, and IL-6↓ 2O2↑ HIF-α, and VEGF↓ 3‧OH, 1O2, Caspase-3, Cleaved Caspase-3, and Bax↑ Bcl-2↓	Alleviates joint swelling, reduces bone erosion, mitigates articular hypoxia and angiogenesis, and decreases serum pro-inflammatory cytokine levels.	Improves hypoxic microenvironment to synergistically enhance SDT efficacy, with dual POD-like and CAT-like activities.	The broad-spectrum antibacterial agent SPX can induce side effects in non-target tissues; Unknown metabolic pathway and long-term toxicity.	[42]
	BMCC NPs	Cu(I)Ce6	RAFLS	CIA mice	O2, 1O2, and ‧OH↑	Reduces clinical joint scores, decreases joint and paw thickness, mitigates bone erosion and cartilage damage, and suppresses synovial hyperplasia.	SDT activated by weak acid and cysteine, reducing off-target toxicity; hypoxia alleviation enhances SDT efficacy.	Long-term in vivo metabolic pathway is unknown; potential biocompatibility risks remain unclear.	[43]
	CUR/O2-MC	CUR	–	CIA rats	1ROS and O2↑ 2HIF-α, IL-6, and TNF-α↓	Ameliorates joint swelling, bone erosion, and synovitis in CIA rats, accompanied by reduced inflammatory factors and HIF-1α.	Natural sonosensitizer with good biosafety; O2 generation enhances SDT efficacy.	Low curcumin bioavailability; unclear in vivo release kinetics of microcapsules.	[44]

3.1. Diagnostic monitoring

3.1.1. PA imaging

Imaging is central to the diagnosis and management of RA; however, conventional radiography and MRI are limited by low sensitivity, lengthy scan times, and frequent false-positive findings, particularly for early joint pathology [97]. PA imaging—an advanced molecular modality—integrates the high resolution of optics with the deep penetration of US, enabling high-contrast, centimetre-deep imaging. Nanoprobes absorb pulsed laser energy and rapidly convert it to heat, producing transient thermal expansion that generates ultrasonic waves detected by a US transducer and reconstructed into high-resolution PA images [[98], [99], [100]]. In RA, functionalized nanoparticles (e.g., RGD peptides targeting FLS or FA targeting macrophages) selectively accumulate in inflamed joints, permitting visualisation of synovial hyperplasia and microvascular lesions. This approach overcomes the sensitivity limitations of conventional imaging for early RA and demonstrates exceptional potential for disease monitoring and therapy assessment.

Venkatesan et al. developed a gold-nanocluster-based theranostic platform (IL-4@AuNCs) (Fig. 8A). FA modification directs the system to M1 macrophages, while loaded IL-4 drives their polarization toward the anti-inflammatory M2 phenotype; a thermosensitive matrix encapsulates the drug, enabling local temperature-triggered release. The plasmonic gold core serves as a dual PA/CT contrast agent, permitting visualisation and quantification of joint inflammation. Long-term in vivo accumulation of gold, however, remains a translational safety concern [29]. PB NPs offer superior theranostic integration: they act as efficient NIR photoacoustic contrast agents and, via their intrinsic multi-enzyme activities, catalytically scavenge ROS, actively modulating the oxidative microenvironment of lesions under image guidance. Chen and co-workers developed a macrophage-membrane-coated nanoplatform (M@P-siRNAs T/I) that combines PB NPs with siRNAs targeting TNF-α and IL-6, thereby coupling gene silencing to ROS scavenging (Fig. 8B). Leveraging the NIR absorption of PB, the system catalytically decomposes H₂O₂ to relieve hypoxia while simultaneously tracking drug accumulation in lesions via real-time PA imaging. In CIA mice, joint blood O₂ saturation rose from 35 % to 92 %, TNF-α and IL-6 expression dropped by approximately 70 % and 65 %, respectively, and bone volume fraction was significantly restored, alleviating arthritis symptoms at multiple levels [30]. Wang et al. developed a controllable artificial nanomedicine (GF–TF) self-assembled from tofacitinib, gallic acid, FA, and ferric ions (Fig. 8C). The resulting metal–polyphenol network displays broadband NIR absorption, and its PA signal is linearly proportional to concentration. In vivo, GF–TF selectively accumulates in inflamed joints and reaches a PA maximum 6 h after injection. Subsequent administration of deferoxamine chelates iron, triggers nanostructure disassembly, and releases the payload in situ, markedly attenuating synovitis and joint destruction, thereby realising imaging-guided precise drug delivery [31].

Fig. 8.

Schematic diagram of nanomaterial design and specific mechanisms for PA imaging in RA treatment. (A) Immuno-modulating theranostic gold nanocages for the treatment of rheumatoid arthritis in vivo. Reprinted from Ref. [29]. Copyright 2022, Elsevier. (B) Photoacoustic image-guided biomimetic nanoparticles targeting rheumatoid arthritis. Reprinted from Ref. [30]. Copyright 2022, PANS. (C) Development of a Controllable Intelligent Drug Delivery System for Efficient Treatment of Rheumatoid Arthritis. Reprinted from Ref. [31]. Copyright 2024, American Chemical Society. (D) In vivo nano contrast-enhanced photoacoustic imaging for dynamically lightning the molecular changes of rheumatoid arthritis. Reprinted from Ref. [32]. Copyright 2021, Elsevier. (E) Inflammation-Responsive Nanoagents for Activatable Photoacoustic Molecular Imaging and Tandem Therapies in Rheumatoid Arthritis. Reprinted from Ref. [33]. Copyright 2024, American Chemical Society. (F) Tocilizumab-Conjugated Polymer Nanoparticles for NIR-II Photoacoustic-Imaging-Guided Therapy of Rheumatoid Arthritis. Reprinted from Ref. [34]. Copyright 2022, John Wiley and Sons. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Compared with the aforementioned inorganic nanomaterials and coordination polymers, endogenous melanin nanoparticles offer a safer alternative for RA theranostics by virtue of their excellent biocompatibility and low immunogenicity. Xiao et al. developed MNP-PEG-RGD, a targeted probe that actively homes to diseased joints via RGD-mediated recognition of αvβ3 integrin (Fig. 8D). Melanin's strong absorption at 680 nm and minimal photobleaching enable stable PA imaging; in AIA mice, lesion signal intensity is 3.36-fold higher than in normal tissue, permitting early RA detection and disease-stage discrimination. The platform also quantifies etanercept efficacy through signal modulation, furnishing a new imaging tool for therapeutic monitoring [32].

Current PA imaging for RA utilises always-on probes, which produce non-specific signals that result in a low signal-to-background ratio (SBR) and false-positive outcomes. To address this, a NO-activated "turn on" probe (TT-BTA) was developed (Fig. 8E). TT serves as a strong electron donor, whereas the weak acceptor BTA limits donor-to-acceptor transfer and intramolecular charge transfer (ICT), producing a weak photoacoustic signal. BTA functions as an NO recognition motif; reaction with NO over-expressed in RA joints converts BTA into the strong acceptor BTT, transforming the structure from "strong donor–weak acceptor" to "strong donor–strong acceptor". This redshifts absorption, intensifies ICT, and generates a new NIR band with an amplified PA response. In CIA mice, the probe achieves an SBR of 7, surpassing conventional probes and discriminating disease severity. Furthermore, dexamethasone is conjugated to a macrophage-membrane coating through a ROS-cleavable thioketal linker; elevated ROS triggers drug release and promotes M1-to-M2 macrophage repolarization, integrating NO-activated imaging with targeted therapy and offering a precise theranostic strategy for RA [33].

Hence, the development of pathological-microenvironment-activatable probes has emerged as a key focus. Although research on RA has primarily focused on NO-responsive systems, the adaptation of well-established microenvironment-responsive strategies from other disease models holds considerable promise. H₂O₂-activatable probes, for instance, amplify inflammatory signals specifically via cleavage of nitrobenzyloxycarbonyl linkers [101], whereas acid-responsive platforms dissociate at low pH to release imaging payloads [102]. These mechanisms mirror the elevated ROS and mild acidity of RA lesions. By engineering smart probes that respond to ROS, pH and other pathological cues, we can create next-generation imaging tools with high SBR and lesion specificity, markedly enhancing the accuracy of early RA diagnosis and in vivo visualisation.

In PA imaging for RA, the probe's excitation wavelength window is likewise a critical determinant of performance. NIR-II excitation reduces tissue scattering and endogenous background, enabling deep and high-SNR imaging [103]. Organic conjugated polymers exhibiting strong NIR-II absorbance and excellent biocompatibility are ideal candidates, exemplified by Chen's TCZ-PNPs that, for the first time, employed NIR-II PA molecular imaging for concurrent RA diagnosis and treatment monitoring (Fig. 8F). To obtain a low band-gap and long-wavelength NIR-II absorption, a donor–acceptor polymer (PBDTBBT) was synthesised employing benzo [1,2-b:4,5-b′] dithiophene (BDT) as donor and dibromobenzo [1,2-c:4,5-c′]bis [1,2,65] thiadiazole (BBT) as acceptor. PBDTBBT was self-assembled with PEG derivatives into polymer nanoparticles (PNPs), and the surface was covalently functionalized with TCZ—an FDA-approved anti-IL-6 receptor (IL-6R) monoclonal antibody—to yield targeted TCZ-PNPs. IL-6R-mediated lesion enrichment enables non-invasive, high-SNR (35.8 dB) 3D PA tomography of inflamed joints. The probe further enables real-time, in vivo tracking of inflammation resolution and therapeutic response. Nevertheless, its complex multi-component architecture and elaborate chemical modifications pose significant challenges to batch-to-batch reproducibility and clinical scalability [34].

3.1.2. PA/FL dual-mode imaging

PA imaging combines optical contrast with deep US penetration, offering high spatial resolution and centimetre-scale depth for anatomical depiction of joints in RA research. Its modest sensitivity, however, limits dynamic metabolic monitoring. FL imaging, by contrast, provides high sensitivity, real-time visualisation, absence of ionising radiation, and simple operation, making it ideal for tracking inflammatory molecular events. Yet severe scattering of excitation and emission light restricts its depth to typically <1 cm, precluding deep-joint assessment. Recent integration of PA and FL dual-modal imaging has opened new avenues: harnessing PA depth with FL sensitivity yields complementary anatomical and molecular information, enhances spatiotemporal accuracy, and furnishes a versatile toolkit for designing targeted, microenvironment-responsive, theranostic probes, progressively overcoming traditional limitations in resolution, penetration, and functional integration [104].

Lan et al. developed an FA-targeted NIR-II dual-modal probe (FA-CF-NPs) and, for the first time, achieved early diagnosis in a mouse RA model using NIR-II FL/PA technology (Fig. 9A). By specifically recognising macrophages, the probe delivered ultra-sensitive imaging (signal-to-noise ratio (SNR) = 15.5) and accurately mapped inflammatory activity during the pre-pathological stage. Dynamic tracking revealed peak probe signal in inflamed joints at 48 h, offering a critical window for early diagnosis and for subsequent PTT/PDT. However, the probe currently lacks therapeutic capability; future conjugation to therapeutic agents could create a theranostic platform [35]. Yu's team innovatively employed neutrophils as biological carriers to construct the GAC@NEs nanoplatform (Fig. 9B), in which cypate exhibits dual NIR absorption peaks at 725 nm and 800 nm, enabling flexible excitation wavelength selection to optimise PA signal and supporting NIR-I/II dual-window PA imaging. Leveraging natural inflammatory chemotaxis, the platform achieves high joint enrichment and, using multimodal imaging, identified 12 h post-injection as the optimal therapeutic time point [36]. Both strategies overcome traditional imaging limitations through active targeting and biological carrier delivery, respectively, providing new technological avenues for early RA diagnosis and precise sequential therapy.

Fig. 9.

Schematic diagram of nanomaterial design and specific mechanisms for PA/FL dual-mode imaging in RA treatment. (A) Folate Receptor-Targeted NIR-II Dual-Model Nanoprobes for Multiscale Visualisation of Macrophages in Rheumatoid Arthritis. Reprinted from Ref. [35]. Copyright 2023, John Wiley and Sons. (B) Neutrophils-mediated bioinspired nanoagents for noninvasive monitoring of inflammatory recruitment dynamics and navigating phototherapy in rheumatoid arthritis. Reprinted from Ref. [36]. Copyright 2024, Elsevier. (C) A multifunctional nanoaggregate-based system for detection of rheumatoid arthritis via Optoacoustic/NIR-II fluorescent imaging and therapy via inhibiting JAK-STAT/NF-κB/NLRP3 pathways. Reprinted from Ref. [37]. Copyright 2023, John Wiley and Sons. (D) In Vivo Evaluation of Liver Injury and Arthritis Enabled by a Nitroxyl-Activated Near-Infrared Fluorescence and Photoacoustic Dual-Modality Imaging Probe. Reprinted from Ref. [38]. Copyright 2025, American Chemical Society.

However, contrast from non-activatable agents is constrained by the lesion-to-background enrichment ratio. Activatable probes overcome these limitations through pathological-microenvironment-responsive mechanisms; upon encountering ROS or nitrated biomarkers overexpressed in RA, their recognition moieties undergo irreversible chemical transformation, activating intense NIR or PA signals and producing a precise "off-to-on" switch. Chen's TPCU@HAT platform employs alendronate-modified HA for dual targeting of macrophage CD44 and bone (Fig. 9C). At the lesion, hyaluronidase and ROS simultaneously cleave the carrier, activating an AIE chromophore (TPY) for multispectral PA and NIR-II FL imaging. The system utilises multispectral photoacoustic tomography (MSOT), an advanced PA modality that combines multi-wavelength excitation with spectral unmixing to discriminate tissue chromophores (haemoglobin, melanin, lipids), enabling accurate signal attribution and 3D anatomical localisation of RA lesions [37]. Liao et al. developed the FPA probe to selectively detect nitroxyl (HNO) (Fig. 9D). Employing a 2-(diphenylphosphinyl) benzoate recognition motif, the probe undergoes oxygen-to-sulfur substitution within the hemicyanine core, red-shifting its absorption by 45 nm. Upon HNO binding, maximal absorption shifts from 650 nm to 760 nm, concurrently activating NIR FL and PA signals. Mitochondrial targeting and passive inflammatory accumulation further endow FPA with precise visualisation capabilities for monitoring disease progression and therapeutic efficacy in inflammatory disorders [38] (Fig. 10).

Fig. 10.

Schematic representation of PA and PA/FL bimodal nanoparticles and their imaging mechanisms for RA diagnosis and treatment.

Although PA and PA/FL dual-modal imaging hold promise for precision diagnosis and treatment of RA, they face multiple clinical-translational challenges, including photobleaching, limited penetration, and probe biosafety. Photostability issues arise from signal decay under laser exposure, which can be mitigated by using AIE-active chromophores, antioxidant modifications, and optimized imaging protocols [37], combined with low-power pulsed lasers and short or intermittent imaging to reduce light dose. Regarding tissue penetration, PA imaging is restricted by tissue scattering and absorption, leading to significant signal attenuation in deep or oedematous regions; interference from endogenous chromophores such as haemoglobin further lowers the SNR. To address this, developing NIR-II-absorbing probes can improve penetration and SNR; coupling multi-wavelength scanning with spectral-unmixing algorithms is expected to achieve accurate signal separation and quantification. Concerning biocompatibility, inorganic materials in current imaging agents pose long-term safety risks, small-molecule dyes exhibit poor photostability, whereas organic conjugated-polymer-based materials offer balanced performance in NIR-II absorption, photostability, and biocompatibility, making them promising candidates. Future efforts should advance degradable materials, systematically evaluate in vivo metabolism and clearance, and optimise targeting and pharmacokinetics through surface modification to facilitate clinical translation.

3.2. SDT

Although PTT and PDT have shown good application prospects in RA therapy, their efficacy is still limited by the limited penetration ability of light sources in biological tissues, making it difficult to effectively act on deep lesion sites. In contrast, US, as a non-invasive and safe energy transmission form, provides a new technical path for precise intervention in deep lesions by virtue of its low attenuation coefficient and large penetration depth during propagation in tissues. Against this background, SDT, a modality derived from the principles of photodynamics and subsequently advanced, has emerged. This technology uses the US as the excitation source to activate sonosensitizers enriched in the lesion area, and promotes massive generation of ROS through mechanisms such as cavitation effects, thereby inducing caspase-dependent apoptosis of diseased immune cells, achieving precise clearance of hyperplastic synovium and effective blocking of inflammatory progression [105]. At present, organic sonosensitizers represented by porphyrins have shown good application potential in SDT research for RA, providing an important material basis for promoting this strategy to the clinic.

3.2.1. Indocyanine-based organic acoustic sensitisers

Indocyanine green (ICG), an FDA-approved NIR dye, exhibits dual photonic and acoustic sensitivity and is applicable to PDT, SDT, and PAI. Tang et al. first evaluated ICG-mediated SDT cytotoxicity against RA-FLS in vitro, marking the initial application of SDT for the treatment of RA. US-activated ICG significantly decreased RA-FLS viability and induced apoptosis via ROS generation; the mechanism involves mitochondrial dysfunction and elevated intracellular ROS. Although molecular details remain elusive, the study validated the feasibility of ICG-SDT for RA [39]. However, the poor photostability and limited targeting capability of ICG lead to off-target toxicity, presenting significant translational challenges.

3.2.2. Porphyrin-based organic acoustic sensitisers

Porphyrins are multifunctional organic compounds that include Photofrin, protoporphyrin IX (PPIX), hematoporphyrin, sodium porphyrin, and meso-tetra (4-methylphenyl) porphyrin. These compounds can generate ROS under light and US excitation. Compared with exogenous dyes such as ICG, PPIX, as an endogenous porphyrin, offers clear metabolic pathways, lower systemic toxicity, controllable synthesis, and good biodegradability. Building on this foundation, Song et al. constructed a Z-scheme heterostructured sonosensitizer for SDT of RA, marking the first such application (Fig. 11A): the system uses bismuth nanotriangle as a carrier coupled with zinc protoporphyrin IX (ZnPP) and is modified with human serum albumin (HSA) to achieve SPARC-protein targeting. Under US activation, the heterostructure exhibits excellent electron–hole separation, produces 24.6 μM O₂, and increases ⋅OH and superoxide anion yields to 8-fold those of the control. Its therapeutic effect is achieved through three synergistic mechanisms: zinc protoporphyrin inhibits HO-1 to weaken antioxidant defence; in situ O₂ generation relieves joint hypoxia; accumulated ROS activate caspase-dependent apoptotic pathways. The system also demonstrates good biocompatibility; bismuth is excreted in urine, and no obvious damage is observed in major organs, indicating high clinical translation potential [40]. Wu et al. developed a macrophage-carrier-based biomimetic sonodynamic platform (Fe₃O₄-PPIX) for targeted delivery to inflamed joints (Fig. 11B). Upon US activation, PPIX generates ROS that disrupt plasma membranes, while Fe²⁺ released from Fe₃O₄ depletes glutathione via the Fenton reaction, synergistically evoking ferroptosis. The innovation exploits the lesion's high H₂O₂ and GSH levels to establish a self-sustaining cycle that self-limits upon substrate consumption, enhancing therapeutic control. Experiments identified 6–12 h post-injection as the optimal therapeutic window; US applied during this window precisely triggers cell death and markedly reduces off-target toxicity, underscoring strong clinical translational potential [41].

Fig. 11.

Schematic diagram of nanomaterial design and specific mechanisms for SDT in RA treatment. (A) Spatiotemporal sonodynamic therapy for the treatment of rheumatoid arthritis based on Z-scheme heterostructure sonosensitizer of HO-1 inhibitor jointed bismuth nanotriangle. Reprinted from Ref. [40]. Copyright 2022, Elsevier. (B) Macrophages-mediated delivery of protoporphyrin for sonodynamic therapy of rheumatoid arthritis. Reprinted from Ref. [41]. Copyright 2022, Elsevier. (C) Mutual-reinforcing sonodynamic therapy against Rheumatoid Arthritis based on sparfloxacin sonosensitizer doped concave-cubic rhodium nanozyme. Reprinted from Ref. [42]. Copyright 2022, Elsevier. (D) Inflammatory microenvironment-responsive “double-insurance” nanoreactors for accurate sonodynamic-chemodynamic therapy of rheumatoid arthritis. Reprinted from Ref. [43]. Copyright 2024, Elsevier. (E) Multi-component Microcapsules Derived Spatiotemporal Sonodynamic Reinforcing Therapy against Rheumatoid Arthritis. Reprinted from Ref. [44]. Copyright 2024, Science Partner Journal.

3.2.3. Other acoustic sensitizers

Upon US activation, sonosensitizers are excited and transfer energy to ³O₂, thereby generating cytotoxic ¹O₂. Hypoxic microenvironments typical of RA severely limit ¹O₂ yield and compromise SDT efficacy. Engineering nanoplatforms that actively modulate local oxygenation to relieve hypoxia has therefore become a key strategy. Li et al. developed concave cubic Rh nanozyme sonosensitizers (Rh/SPX-HSA) that achieve SPARC-mediated inflammatory targeting via HSA (Fig. 11C). The platform operates through dual catalysis: sparfloxacin (SPX) produces ¹O₂ under US to trigger apoptosis, while Rh nanozymes catalyse H₂O₂-to-•OH conversion for direct cytotoxicity and decompose H₂O₂ to evolve O₂, alleviating hypoxia. SPX-mediated cavitation accelerates Rh catalysis, and evolved O₂ further boosts ¹O₂ production, establishing a self-amplifying loop. In CIA mice, arthritis scores fell from 12 to 4, bone density increased by 30 %, and IL-1β levels dropped by nearly 50 %, confirming anti-inflammatory and osteoprotective efficacy. However, Systemic SPX side-effects and long-term Rh biodistribution require optimisation of targeted delivery and comprehensive metabolic assessment [42]. Zhou et al. engineered BMCC, a copper-doped ZIF-8 nanoreactor that targets lesions through bovine serum albumin (BSA)–SPARC affinity (Fig. 11D). The platform exhibits dual acid/enzyme responsiveness: under inflammatory acidity, ZIF-8 degrades, releasing Cu(II)Ce⁶ that reacts with over-expressed cysteine to yield sonosensitive Cu(I)Ce⁶; concurrently, BSA-MnO₂ decomposes H₂O₂ to evolve O₂ and relieve hypoxia, while released Cu²⁺ produces •OH via a Fenton-like reaction, mediating synergistic SDT/Chemodynamic therapy (CDT). BMCC displayed potent efficacy and an acceptable safety profile in CIA mice, yet the long-term metabolism and biocompatibility of copper and manganese ions require systematic assessment [43].

In response to the biosafety issues of metal-based sonosensitizers, research focus is gradually shifting toward natural-origin sonosensitizers with better biocompatibility. Against this background, curcumin (CUR), as a natural molecule with sonosensitizing activity, offers new possibilities for advancing the clinical translation of SDT. Huang's team constructed a core–shell microcapsule system (CUR/O₂-MCs), with a CUR-loaded hydrogel shell and an O₂-rich perfluorocarbon core (Fig. 11E). Upon US triggering, the system releases O₂ through perfluorocarbon phase transition, synergistically enhancing the sonodynamic effect of CUR and forming an "O₂-supply & efficacy-boost" mechanism: generated ROS induce synovial cell apoptosis, while CUR and O₂ jointly promote macrophage polarization toward the anti-inflammatory M2 phenotype. In the CIA model, this treatment significantly ameliorates joint swelling and bone erosion and reduces inflammatory cytokine levels. However, the system still faces challenges such as low CUR bioavailability, unclear release kinetics, and unverified perfluorocarbon metabolic pathways, necessitating further assessment of its long-term safety [44] (Fig. 12).

Fig. 12.

Schematic diagram of SDT nanoparticle-mediated induction of apoptosis in proliferative synovium for RA treatment.

Beyond energising SDT, the US's mechanical effects uniquely enhance targeted drug delivery. Xiao et al. exploited US-induced sonoporation to reversibly permeabilise cell membranes, increasing arthritic accumulation of drug-loaded extracellular vesicles by 40 % versus untreated controls. This physical boost synergises with the vesicles' intrinsic targeting to promote anti-inflammatory macrophage polarization and suppress osteoclastogenesis. Without the US, the same carriers retain baseline tropism but exhibit markedly lower catalytic activity and therapeutic efficacy, accompanied by greater hepatic sequestration [106]. Thus, the US serves a dual role in RA management—activating sonosensitisers and amplifying delivery—thereby opening new avenues for precision therapy.

At present, research on the application of SDT to RA treatment remains relatively limited; reported nanoplatforms generally suffer from low targeting efficiency, weak US absorption, and unresolved long-term safety. To overcome these hurdles, sono-photodynamic therapy has emerged as a promising synergistic strategy that merges photodynamic and sonodynamic merits to produce robust ROS at low doses and treat deep lesions. For example, ZnSnO₃@UCNPs sono-photosensitizers exploit energy transfer and piezoelectricity to markedly boost ROS generation under concurrent NIR and ultrasound excitation [107]. Future efforts should focus on designing biodegradable sono-photosensitizers with high ROS output, standardising US parameters, and implementing image-guided, patient-specific protocols to enhance therapeutic precision and safety.

4. Gas therapy

Phototherapy and sonotherapy hold considerable promise for RA, yet both modalities face constraints in tissue penetration, activation efficiency, and microenvironmental compatibility. Hypoxia within inflamed joints severely limits ROS generation in PDT and SDT, diminishing therapeutic efficacy. In this context, gas therapy offers a route to enhance these treatments by supplying O₂ in situ and relieving hypoxic stress. As an emerging strategy, gas therapy combines low toxicity, high biocompatibility, and unique biological regulatory functions, providing innovative solutions to overcome current bottlenecks in photonic and acoustic therapeutic applications [108]. Gas therapy mainly utilises gas molecules such as O₂, H₂, NO, CO, and H₂S, which play important roles in regulating inflammation, oxidative stress, and immune responses. However, gaseous molecules have a short half-life and rapid diffusion rate in vivo, limiting their effective accumulation at lesion sites [109]. Consequently, the development of nanocarriers with controllable size and suitable properties has emerged as a strategic research frontier in precision nanomedicine. These nanomaterials enable controlled release, prolong gas activity, and increase gas local concentration at inflamed joints through in situ generation, loading, or encapsulation of gas molecules or their precursor drugs. They can be activated by endogenous stimuli (for example, glutathione (GSH) and H₂O₂) or exogenous stimuli (for example, light and heat), enabling targeted accumulation and precise, controlled gas release at inflamed joints (Table 4) (Fig. 13).

Table 4.

Summary of current gas therapy nanosystems for RA therapy.

Gas	Nano-system	Generation NPs	Targets	Animal model	Mechanisms	Effects	Key features	Limitations	Refs.
O2	CMP	PCC 7942	–	CIA mice	1O2↑ HIF-α↓ 2IL-6 and IL-1β↓	Elevates articular O2 levels, shifts macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, and alleviates joint inflammation, swelling, and bone erosion.	Spatiotemporally precise O2 generation; good biosafety.	Limited long-term O2 generation and challenging scale-up production.	[45]
	Psoralen gel	Calcium peroxide	MMPs-response	CIA rats	1O2↑ HIF-α↓ 2TNF-α, IL-1β, IL-6, IL-17, and IFN-γ↓	Reduces joint swelling, mitigates bone damage, decreases paw thickness and clinical scores, and ameliorates metabolic dysregulation in RA rats.	Pathological microenvironment-responsive release; dual anti-inflammatory and bone-protective effects.	Limited drug loading capacity; potential toxicity risk of calcium peroxide.	[46]
	Leo@CAT@NM-Lipo	CAT	NM (neutrophils)	AIA rats	1O2↑ HIF-α↓ 2iNOS↓ Arg-1↑ 3Aggrecan and Sox9↑ MMP9↓ TNF-α, IL-1β, IL-6, CCL2, and CCL5↓ IL-10↑	Effectively alleviates joint inflammation and erosion, reduces arthritis scores and paw swelling, restores rat body weight, and mitigates bone and cartilage damage.	Strong targeting capability; ROS-responsive drug release; good biocompatibility.	Challenging manufacturing process.	[47]
	BSA-BR-Pt NPs	Pt	–	CIA mice	1O2↑ HIF-α and ROS↓ 2Glycolysis↓ OXPHOS↑	Significantly reduces paw thickness, joint diameter, synovitis scores, and bone erosion area in mice, effectively alleviating joint inflammation, cartilage damage, and osteolysis.	Synergistic hypoxia alleviation and ROS scavenging.	Unclear biosafety and long-term toxicity; insufficient drug delivery efficiency and targeting.	[48]
	Fh-PVP	Fe5HO8·4H2O	–	AIA mice	1O2↑ HIF-α, IL-6, IL-1β, and TNF-α↓ 2Arg-1 and IL-10↑	Markedly reduces joint swelling, decreases oxidative stress markers, protects articular bones from inflammatory damage, and inhibits cartilage erosion.	High catalytic activity in acidic environments; dual-function regulation (antioxidant/oxygenation); good biocompatibility.	Low crystallinity potentially compromises long-term stability and catalytic efficiency is still inferior to natural enzymes.	[49]
	ε-PLE@MnCoO/Gel Hydrogel	MnCoO	–	RA rabbits	1O2↑ HIF-α↓ 2IL-6, IL-1β, TNF-α, PGE2, and NO↓	Alleviates localized hyperinflammation and synovial hyperplasia, reduces ROS levels and oxidative stress, enhances prosthesis osseointegration, and promotes bone regeneration.	Dual ROS scavenging and H2O2-driven O2 production; strong catalytic stability.	Unclear long-term biosafety and potential effects of in vivo degradation products.	[49]
	MnO2-motor NPs	MnO2	–	CIA rats	1O2↑ HIF-α↓ 2IL-6, TNF-α, and iNOS↓ 3Arg-1, IL-10, and CD206↑	Effectively controls inflammation, modulates macrophage phenotype switching, alleviates joint hypoxia, and reduces bone damage and cartilage degradation.	H2O2-driven nanomotor in RAM enables ROS scavenging, O2 generation/imaging, and enhanced diffusion.	Challenges in precision control over movement and depth, and unknown long-term safety profile.	[50]
	Au@CeO2	CeO2	–	CIA mice	1O2↑ HIF-α↓ 2IL-6, IL-1β, and TNF-α↓	Improves joint hypoxia, suppresses ankle thickness progression, promotes weight recovery in mice, and mitigates bone erosion, synovitis, and cartilage degradation.	High photothermal conversion efficiency.	Potential long-term toxicity risks.	[51]
	MTX-loaded MFC-MSNs	Manganese ferrite NPs	–	AIA rats	1O2↑ HIF-α and ROS↓ 2IL-6, TNF-α, and iNOS↓ 3Arg-1, IL-10, and CD206↑	Effectively alleviates joint hypoxia, inflammation, and pathological symptoms while modulating macrophage phenotype switching.	Synergistic effect: ceria NPs eliminate ·OH intermediates from manganese ferrite NPs' O2 generation.	Unclear long-term biosafety and inadequate targeting capability.	[52]
	M2CPR	CuS	Macrophage	CIA mice	1TNF-α、IL-1β、IL-17↓ 2O2↑ ROS↓ 3IL-10、TGF-β↑	Targeted intra-articular O2 delivery reverses hypoxia, sensitizes activated T cells to cuproptosis, and thereby relieves RA inflammation and bone erosion.	Dual-action mechanism: immunosuppression and cytotoxicity; intelligent activation-responsive therapeutic strategy; high biocompatibility.	Long-term safety and pharmacokinetics remain to be established; mechanistic complexity.	[53]
H2	Mg−HA-motor	Mg	–	CIA rats	1H2↑ ROS↓ 2IL-6, IL-1β, and TNF-α↓ 3MMP-3 and MMP-9↓	Reduces local oxidative stress, downregulates inflammatory factors, decreases joint diameter, and alleviates synovitis and cartilage erosion.	Synergistic therapy and active propulsion; ultrasound imaging capability.	Water-dependent reaction with limited persistence; manufacturing complexity.	[54]
	R-Au/TiO2	TiO2	Macrophage	CIA mice	1H2↑ ROS↓ 2IL-6, IL-1β, and TNF-α↓	Alleviates inflammatory responses, reduces cartilage degradation, synovial hyperplasia, and inflammatory cell infiltration.	Plasmon-enhanced photocatalysis, significantly boosted H2 production and ROS scavenging.	Complex synthesis and non-biodegradability of gold nanorods.	[55]
	Pt-MOF@Au@QDs/PDA NPs	Pt-MOF	FLS	CIA mice	1H2↑ ROS↓ 2IL-6 and TNF-α↓	Alleviates oxidative stress in RA mice, significantly mitigates joint damage, and suppresses overall arthritis severity.	High drug loading; on-demand activation; PA imaging capability; combined PTT.	Costly materials and complex synthesis; unknown long-term metabolic fate.	[56]
	CSNs	CaSi2	–	AIA mice/AIA Rabbits	1H2↑ ROS↓ 2IL-6 and TNF-α↓ IL-10 and TGF-β↑	Significantly alleviates joint swelling, mitigates bone erosion, and exerts synergistic antioxidant, anti-inflammatory, and bone-remodelling effects.	Antioxidant and anti-inflammatory with bone homeostasis regulation; good biocompatibility.	Large-scale production challenges; individual variations affect hydrolysis efficiency.	[57]
CO	TC@AI NPs	TTCO	IL-6R/ROS-response	CIA mice	1CO, HO-1, and JAK-STAT↑ MAPK, NF-κB, and P13K-Akt↓ 2IL-6, TNF-α, and iNOS↓ CD206↑	Effectively reverses RA-induced bone erosion, alleviates joint inflammation, and restores immune homeostasis.	On-demand activation; well-defined structure with high reproducibility; NIR-II imaging.	Long-term safety remains unknown.	[58]
	BM	3-HF	Macrophage	AIA rats	1CO and HO-1↑ iNOS↓ 2NO, Nitrite, TNF-α, and IL-6↓	Alleviates arthritis symptoms, inhibits bone corrosion, and repairs damaged bone and cartilage.	Precise NO/CO co-modulation, multi-pathway anti-inflammatory synergy.	Stability and scale-up challenges of micelles.	[59]
H2S	BDMA NGs	DATS	Macrophage	CIA mice	1H2S and Nrf2-Keap-1↑ HIF-1α and ROS↓ 2IL-6, IL-1β, and TNF-α↓ IL-10↑	Reduces joint inflammation and repairs degeneration by alleviating symptoms, lowering biomarkers, and restoring macrophage homeostasis.	GSH-responsive on-demand activation; NIR-II FL/PA imaging.	Precise control of gas therapy; unclear long-term metabolic pathway.	[60]

Fig. 13.

Schematic diagram of nanomaterials in gas-based therapy for RA.

4.1. O₂

The hypoxic environment in the joint cavity of patients with RA is a key factor contributing to disease progression [110]. This hypoxia exacerbates the inflammatory response and joint damage and reduces the efficacy of most RA therapies, including pharmacologic therapy, surgical therapy, PTT, PDT, and SDT. Therefore, alleviating hypoxia in the joint cavity and scavenging excess ROS are critical for enhancing treatment outcomes. To address these challenges, nanomedicine-based O₂ delivery systems have been developed. These systems aim to enhance the efficacy of existing treatments by alleviating hypoxia within the joint cavity. Current strategies focus on two main approaches: (1) efficient O₂ delivery to the joint cavity using gas carriers and (2) localised O₂ generation through catalytic decomposition of H₂O₂ in the joints. Both strategies relieve hypoxia and regulate redox balance, thereby inhibiting inflammatory responses and joint damage.

4.1.1. Using gas carriers to deliver O₂

Typically, carrier systems used to deliver O₂ directly to RA joints are designed to release free O₂ molecules in a controlled manner in response to specific stimuli.

Guo et al. developed a cyanobacterial micro-nano device (CMP) in which lanthanide up-conversion nanoparticles (UCNPs) convert NIR light into blue light to drive cyanobacterial photosynthesis for sustained O₂ generation (Fig. 14A). Encapsulated within a thermosensitive hydrogel, CMP forms an in situ gel that prolongs joint residence. The evolved O₂ down-regulates HIF-1α, shifts macrophages from the M1 to the M2 phenotype, and synergistically potentiates the anti-inflammatory action of methotrexate, effectively alleviating arthritis symptoms and bone erosion [45]. However, cyanobacteria exhibit short in vivo survival, thereby limiting sustained O₂ production. Consequently, carrier optimisation or genetic engineering is required to extend their lifespan and metabolic activity.

Fig. 14.

Schematic diagram of O₂ therapy for RA based on in situ generation of nanomaterials and endogenous enzyme systems. (A) NIR-Responsive Spatiotemporally Controlled Cyanobacteria Micro-Nanodevice for Intensity-Modulated Chemotherapeutics in Rheumatoid Arthritis. Reprinted from Ref. [45]. Copyright 2021, American Chemical Society. (B) A Metabolic Driven Bio-Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis. Reprinted from Ref. [46]. Copyright 2023, John Wiley and Sons. (C) Neutrophil-Mimetic, ROS Responsive, and Oxygen Generating Nanovesicles for Targeted Interventions of Refractory Rheumatoid Arthritis. Reprinted from Ref. [47]. Copyright 2023, John Wiley and Sons. (D) Synergistic rheumatoid arthritis therapy by interrupting the detrimental feedback loop to orchestrate hypoxia M1 macrophage polarization using an enzyme-catalyzed nanoplatform. Reprinted from Ref. [111]. Copyright 2024, Elsevier.

Wang et al. developed a degradable hydrogel platform by incorporating psoralen and small particle size calcium peroxide into triglyceride monostearate (TGMS) hydrogels (Fig. 14B). At the RA joints, overexpressed MMPs cleaved the ester bonds in TGMS, leading to the slow degradation of the hydrogel. The encapsulated calcium peroxide was gradually exposed and reacted with water in the surrounding environment, leading to sustained O₂ release, which prevented localised ROS accumulation, preserved redox balance, inhibited HIF-1α expression, and alleviated joint inflammation and injury [46].

4.1.2. Catalyzing H₂O₂ in RA joints

Pathological accumulation of ROS is a key feature of RA lesions. Persistent ROS accumulation aggravates synovial inflammation and accelerates bone erosion by activating the NF-κB signalling pathway [112]. Current strategies for ROS scavenging involve two catalytic systems: endogenous enzyme systems (for example, CAT) to regulate ROS metabolism through disproportionation reactions and engineered nanoenzyme mimics based on metals such as Mn, Fe, and Au. For example, Tang et al. developed neutrophil-membrane-camouflaged nanoliposomes that target inflamed joints through inherent neutrophil chemotaxis (Fig. 14C). Loaded catalase catalytically decomposes ROS to evolve O₂, relieving hypoxia, while released leonurine suppresses synovial activation by down-regulating NF-κB/MAPK signaling and modulates the Treg/Th17 balance. In AIA rats, arthritis scores fell from 11.2 to 5.2, paw swelling decreased by 55.6 %, bone density and hepatic/renal function improved, and oxidative stress and hypoxia were markedly attenuated. The platform exhibits favourable biosafety, yet long-term in vivo metabolism warrants further investigation [47]. Guo et al. developed a bioengineered enzymatic nanoplatform, BSA-bilirubin-platinum nanoparticles (BSABR-Pt NPs), that modulates hypoxia and oxidative stress (Fig. 14D). In this system, bilirubin mediates potent ROS scavenging, while platinum nanoparticles offer dual catalytic activity by neutralising ROS and generating O₂ to reduce hypoxia. This coordinated mechanism disrupts the hypoxia-oxidative stress cycle, reprogramming macrophages toward anti-inflammatory phenotypes and alleviating RA inflammation [111].

Iron-based nanomaterials with peroxidase-like activity, metal-organic framework (MOF) derivatives, manganese dioxide, and cerium dioxide nanoparticles can be used to catalyse H₂O₂ [113]. Yang et al. developed iron-oxygen hydroxide nanoparticles (Fh-PVP) with tetra-coordinated iron sites that facilitate proton transfer and O₂ generation, showing CAT-like activity for RA treatment (Fig. 15A) [48]. Zhao et al. developed a nanoenzyme-enhanced hydrogel containing Mn₃[Co(CN)₆]₂ MOF-derived mesoporous manganese cobalt oxide (Mn_1.8Co_1.2O₄ = MnCoO) nanoenzymes (Fig. 15B). The hydrogel system efficiently catabolized endogenous H₂O₂ and produced O₂. Its unique physicochemical properties enable its use as an injectable delivery vehicle for bone marrow mesenchymal stem cells, effectively shielding transplanted cells from ROS-induced cytotoxicity and hypoxia-compromised viability while mitigating osteogenic differentiation impairment under pathological stress conditions [49]. Bone marrow mesenchymal stem cells can differentiate into chondrocytes and osteoblasts, thereby promoting bone regeneration and reducing inflammation [114]. Xu et al. developed an H₂O₂-driven MnO₂ nanomotor system (MnO₂-motor) that alleviates hypoxia and scavenges ROS (Fig. 15C). The MnO₂ nanoparticles continuously decompose H₂O₂ to generate O₂, which suppresses M1 polarization of macrophages and slows disease progression. The degradation product, Mn²⁺, is biocompatible and excreted via hepatic and renal pathways. Importantly, the O₂ release alters acoustic impedance, enabling ultrasound detection of O₂-driven echo signals in the joint cavity of CIA rats. This response correlates with arthritis severity, providing a real-time diagnostic readout of disease activity [50]. Wang et al. developed an NIR-responsive metal/semiconductor nanocomposite comprising polyethene glycol-modified cerium-shelled gold nanorods (Au@CeO₂). Localized surface plasmon resonance-mediated light confinement significantly amplified photothermal conversion efficiency under laser irradiation. The generated hyperthermia selectively ablated hyperproliferative inflammatory cells infiltrating arthritic joints and activated CeO₂ catalase-mimetic activity, catalyzing H₂O₂ decomposition into molecular O₂ to ameliorate hypoxia while disrupting pathological oxidative stress cascades [51]. Kim et al. developed MFC-MSNs, a synergistic nanoenzyme system capable of scavenging ROS and generating O₂ (Fig. 15D). Manganese ferrite NPs generate ‧OH as intermediates during O₂ production via the Fenton reaction, while cerium nanoparticles effectively scavenge it. These complementary interactions alleviate inflammation by polarising macrophages from the M1 to M2 phenotype in RA-affected knee joints [52]. Wu et al. developed M2Exo@CuS-CitP-Rapa (M2CPR), a multifunctional nanocomplex for RA immunomodulation (Fig. 15E). The system leverages M2 macrophage exosomes for targeted delivery of CuS nanoparticles to inflamed joints. CuS exhibits catalase activity, rapidly decomposing H₂O₂ to generate O₂ within 5 min in the acidic RA microenvironment, which triples local O₂ levels and reverses hypoxia. Following M2CPR treatment, HIF-1α expression decreased by 47 %, while O₂ saturation rose from 18 % to 42 %. This localized oxygenation suppresses HIF-1α-driven inflammation and enhances mitochondrial respiration in activated T cells, sensitizing them to cuproptosis. In CIA mice, M2CPR outperformed single-component therapies, providing a novel approach to modulate immune metabolism via on-site O₂ generation [53].

Fig. 15.

Schematic diagram of metal-based engineered nanozymes for RA treatment via CAT decomposition of H₂O₂ to generate O₂. (A) Ferrihydrite Nanoparticles Alleviate Rheumatoid Arthritis by Nanocatalytic Antioxidation and Oxygenation. Reprinted from Ref. [48]. Copyright 2023, American Chemical Society. (B) Nanozyme-reinforced hydrogel as a H₂O₂-driven oxygenerator for enhancing prosthetic interface osseointegration in rheumatoid arthritis therapy. Reprinted from Ref. [49]. Copyright 2023, Springer Nature. (C) Arthritic Microenvironment Actuated Nanomotors for Active Rheumatoid Arthritis Therapy. Reprinted from Ref. [50]. Copyright 2022, John Wiley and Sons. (D) Synergistic Oxygen Generation and Reactive Oxygen Species Scavenging by Manganese Ferrite/Ceria Co-decorated Nanoparticles for Rheumatoid Arthritis Treatment. Reprinted from Ref. [52]. Copyright 2019, American Chemical Society. (E) Engineering M2 macrophage-derived exosomes modulate activated T cell cuproptosis to promote immune tolerance in rheumatoid arthritis. Reprinted from Ref. [53]. Copyright 2025, Elsevier.

Currently, nanoplatforms for O₂ therapy in RA have evolved from simple O₂ generators into multi-mechanistic, synergistic systems. Biological carriers exhibit excellent biocompatibility and targeting, offering clear translational potential; inorganic nanozymes afford high catalytic efficiency and functional diversity but confront long-term safety and scalability hurdles; externally stimulated systems enable on-demand O₂ release yet are constrained by tissue penetration and device dependence. Future efforts should prioritise smart-responsive nanomaterials that release O₂ precisely in response to intra-articular inflammatory cues, achieving on-demand oxygenation. Integrating this strategy with immunomodulators will create synergistic regimens that correct immune dysregulation while remodelling the microenvironment. Concurrent design of biodegradable carriers and rigorous long-term safety assessment will accelerate clinical translation.

4.2. H₂

H₂ therapy is gaining rapid momentum as an emerging therapeutic strategy for inflammatory diseases. H₂ selectively scavenges free radicals, particularly ‧OH, converting them into H₂O. In addition to its remarkable anti-inflammatory and antioxidant properties, it is widely used in anti-free radical therapy, especially when combined with nanomedicines [115]. However, the specific mechanism of action of H₂ in RA has not been fully elucidated and requires further investigation. In addition, current nanoplatform technologies for H₂ generation and release are still under development, with most strategies relying on nanocarriers to generate H₂ in situ at lesion sites for targeted and efficient delivery.

Xu et al. developed a biocompatible magnesium micro-motor coated with hyaluronic acid (Mg-HA motor), wherein magnesium reacts with water in joints to continuously produce H₂ (Fig. 16A). The locally generated H₂ bubbles act as a propellant for movement and as an active ingredient for scavenging ROS and suppressing inflammation. The motor significantly reduced the expression of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β in CIA rats, and the pathological and immunohistochemical results suggested that the H₂ attenuated synovial inflammation and cartilage erosion in the joints [54]. Li et al. developed RGD-peptide-functionalized Au/TiO₂ nano-dumbbells for targeted H₂ generation in inflamed joints (Fig. 16B). Under NIR irradiation, plasmon-induced hot electron transfer occurred at the AuNRs-TiO₂ interface, where hot charge carriers generated via localized surface plasmon resonance were directionally injected into TiO₂ for spatially controlled photocatalytic H₂ evolution. The AuNR-TiO₂ Schottky heterojunction enhanced charge separation efficiency through built-in electric field effects, thereby amplifying H₂ generation. The in situ-produced H₂ exerted anti-inflammatory effects by suppressing pro-inflammatory cytokine release and attenuating inflammasome activation in synovial macrophages. In CIA mice, H₂ treatment mitigated joint inflammation, reducing cartilage erosion, synovial hyperplasia, and inflammatory cell infiltration [55]. Metal-organic frameworks, a class of semiconductor-like porous materials, are of great potential in photocatalytic H₂ production. Pan et al. designed a Pt-MOF@Au@QDs/PDA smart H₂ nanogenerator, which introduces metal nanoparticles, Pt and Au, into MOFs and expands the light-absorbing ability of MOFs from the UV region to the visible and even the NIR region (Fig. 16C). Thus, it exhibits highly efficient photocatalytic H₂ production under visible light irradiation and enhances the buffering effect against oxidative stress in synovial cells [56]. In response to the limitations of existing therapies that focus on inflammation control but fail to simultaneously reestablish bone microenvironment homeostasis, Ji et al. constructed a novel therapeutic system using 2D layered calcium disilicide nanoparticles (CSNs) (Fig. 16D). This nanosystem produces a triple synergistic effect through controlled hydrolysis. First, the released H₂ effectively removes excess ‧OH and regulates macrophage repolarization. Second, the generated alkaline Ca(OH)₂ neutralizes the acidic microenvironment in the focal area and significantly inhibits osteoclast activity. In addition, the continuously released Ca²⁺ complexes with local phosphates in situ and promote bone matrix mineralisation through the heterogeneous nucleation mechanism of Ca₃(PO₄)₂. This multi-targeted therapeutic strategy, which combines anti-inflammatory microenvironment remodelling with the promotion of synchronous bone repair, offers a new research direction for the treatment of RA-related bone destruction [57].

Fig. 16.

Schematic diagram of nanomaterial design and specific mechanisms that generates H₂ in RA treatment. (A) Magnesium-Based Micromotors as Hydrogen Generators for Precise Rheumatoid Arthritis Therapy. Reprinted from Ref. [54]. Copyright 2021, American Chemical Society. (B) Gold nanorods with spatial separation of TiO₂ deposition for plasmonic effect and Schottky junction enhanced antioxidant stress and hydrogen therapy of rheumatoid arthritis Reprinted from Ref. [55]. Copyright 2023, Elsevier. (C) Octahedral Pt-MOF with Au deposition for plasmonic effect and Schottky junction enhanced hydrogenothermal therapy of rheumatoid arthritis. Reprinted from Ref. [56]. Copyright 2022, Elsevier. (D) Hydrolysis of 2D Nanosheets Reverses Rheumatoid Arthritis Through Anti-Inflammation and Osteogenesis. Reprinted from Ref. [57]. Copyright 2024, John Wiley and Sons. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

4.3. CO

CO is a therapeutic gas with anti-inflammatory properties. The biological effects of CO are significantly concentration-dependent. At low concentrations, CO exerts its physiological cytoprotective function and maintains homeostatic regulation of the internal environment through specific binding to heme-containing proteins (for example, soluble guanylate cyclase and cytochrome c oxidase). Low doses of exogenous CO exhibit significant therapeutic potential in various disease models, including inflammatory diseases such as RA, cardiovascular disease, infectious disease, and organ transplant rejection [116]. CO can significantly enhance therapeutic outcomes in RA by inducing the expression of the anti-inflammatory enzyme heme oxygenase-1 (HO-1) and regulating key inflammatory signalling pathways such as MAPK and NF-κB [117,118]. Specifically, CO enhances the antioxidant and anti-inflammatory activities of HO-1 by upregulating its expression; meanwhile, it reduces the release of pro-inflammatory cytokines (for example, TNF-α, IL-1β, and IL-6) by inhibiting the activation of MAPK and NF-κB signalling pathways, thereby alleviating joint inflammation and slowing disease progression. However, when CO concentration is too high, owing to its strong affinity for Hb (about 200–250 times that of O₂), it competitively inhibits the O₂-binding ability of Hb, leading to tissue hypoxia and, in severe cases, CO poisoning or even death. Therefore, precise regulation of CO concentration and accurate delivery to inflamed joints are crucial for maximising its therapeutic effects on RA and avoiding toxicity. Zhang et al. synthesised a novel nanoprobe (TTCO) and coupled an anti-interleukin-6 receptor antibody to the nanoprobe to provide an active RA-targeting capability (Fig. 17A). Under inflammatory ROS conditions, the manganese carbonyl group of the probe undergoes cleavage to release the therapeutic gases CO and AIE luminophores (TT), achieving seamless integration of ROS scavenging and CO-releasing functions for combined RA treatment. The nanoformulation significantly inhibited pro-inflammatory factors, promoted macrophage polarization from the M1 to M2 phenotype, and significantly alleviated RA symptoms and joint destruction [58]. The onset and progression of inflammation-related diseases, such as arthritis and inflammatory bowel disease, are closely associated with abnormally elevated NO concentrations. Excess NO promotes the release of inflammatory mediators, exacerbating tissue damage and disease progression. However, endogenous low concentrations of CO are effective in suppressing the inflammatory response through various mechanisms. Tao et al. designed a biomimetic “respiratory” micelle (Fig. 17B). This micellar core, which contains NO-responsive ophenylenediamine (oPDA) and CO-releasing 3-hydroxyflavone (3-HF) motifs, can spontaneously “inhale” pro-inflammatory NO and “exhale” anti-inflammatory CO under visible light irradiation. In the AIA rat, the “respiratory” micelles were more effective in repairing bone damage than single-component micelles that only “inhaled” NO and “exhaled” CO, as well as the clinically used dexamethasone control group. The “breathing” micelles more effectively repaired bone damage, relieved inflammatory joints, and demonstrated superior anti-inflammatory properties [59].

Fig. 17.

Schematic diagram of nanomaterial design and specific mechanisms that generates CO or H₂S in RA treatment. (A) Microenvironment-Activatable Probe for Precise NIR-II Monitoring and Synergistic Immunotherapy in Rheumatoid Arthritis. Reprinted from Ref. [58]. Copyright 2024, John Wiley and Sons. (B) Breathing Micelles for Combinatorial Treatment of Rheumatoid Arthritis. Reprinted from Ref. [59]. Copyright 2022, John Wiley and Sons. (C) In-situ GSH-responsive gas nanogenerator for active NIR-II FL/PA imaging and synergistic restoration the macrophage niche in rheumatoid arthritis. Reprinted from Ref. [60]. Copyright 2024, Elsevier.

4.4. H₂S

H₂S is the third endogenous gaseous signalling molecule, following NO and CO, with established anti-inflammatory therapeutic effects in multiple inflammatory disorders. H₂S exhibits a dual role in inflammation therapy, and its effects are concentration-dependent. At higher concentrations, H₂S may cause cellular damage because of its toxic effects on cells, including free radical generation and glutathione depletion. However, in the treatment of osteoarthritis, exogenous H₂S and its donors (for example, NaHS and GYY4137) exhibit significant anti-inflammatory potential [119]. To circumvent the potential toxicity associated with direct inhalation of H₂S, researchers have developed a variety of H₂S donor compounds. Currently, commonly used H₂S donors include exogenous sources such as sodium hydrosulfide (NaHS), diallyl trisulfide (DATS), GYY4137, and dithiocarbamate derivatives (DTCs), and endogenous sources such as L-cysteine, homocysteine, and thiosulfate [120]. However, achieving precise delivery and controlled release of H₂S in the RA region remains a major challenge. Zheng et al. designed multifunctional GSH-responsive H₂S nanogenerators (BDMA NGs), which passively target RA joints through the enhanced leakage and retention (ELVIS) effect and rapidly respond to reduced GSH to generate H₂S (Fig. 17C). H₂S effectively inhibited HIF-1α expression and triggered the Nrf2-Keap1-ARE signalling pathway, which accelerated macrophage M1/M2 phenotypic transition and improved the RA microenvironment [60].

Among the four gases described, O₂ directly relieves joint hypoxia—the core pathophysiology of RA—thereby creating conditions that improve the microenvironment and potentiate adjunctive therapies. H₂, with excellent biosafety and selective ‧OH scavenging, confers distinctive antioxidant benefits. CO and H₂S modulate key inflammatory pathways at low concentrations, yet exhibit narrow therapeutic windows and concentration-dependent hazards: high-level CO impairs O₂ transport by competitively binding haemoglobin, whereas H₂S can be either pro- or anti-inflammatory. Future efforts must develop more accurate delivery systems or novel donor molecules to overcome these limitations. Importantly, the biological actions of these gases are not isolated; their signalling pathways show extensive crosstalk and competitive interactions that must be considered when designing combination regimens. CO and O₂ compete for haemoglobin—high CO evokes tissue hypoxia that can be offset by appropriate O₂ levels—while CO and H₂S share NF-κB/MAPK targets, offering either synergistic anti-inflammatory effects or pathway competition. H₂ radical-scavenging may complement the antioxidant actions of H₂S and CO and modulate their redox networks. Elucidating these interactions will enable chronologically controlled, dose-precise combination strategies that amplify synergy, avert competitive inhibition and cumulative toxicity, and advance precision and safety in RA therapy (Fig. 18).

Fig. 18.

Schematic diagram of therapeutic mechanisms in gas-based therapy for RA.

5. Combined treatment

5.1. Synergistic PTT/PDT/gas therapy

Monotherapies often fail to address the complex pathological milieu of RA, prompting the development of multimodal combination strategies. Among these, phototherapy coupled with gas therapy holds considerable promise. Photothermal ablation not only eradicates diseased tissue but also facilitates gas-molecule penetration and release, thereby amplifying therapeutic outcomes. Concurrent gas therapy alleviates intra-articular hypoxia and inflammation, while protecting normal tissues from excessive ROS. Characterised by precise targeting, minimal invasiveness, and high efficacy, this multimodal approach opens new avenues for RA management.

Fu et al. developed MPM@Lipo, a dopamine-liposome nanosystem that accumulates in inflamed joints via the ELVIS targeting mechanism (Fig. 19A). The platform offers three functions: near-infrared photothermal ablation of inflammatory cells, MnO₂-catalyzed H₂O₂ decomposition to relieve hypoxia, and H₂O₂-responsive release of methotrexate for precise chemotherapy. This photothermal/O₂-therapy/chemotherapy synergy provides a new regimen for RA, but suffers from sub-optimal targeting, requiring further refinement [61]. Chen et al. developed MAHI NGs, an endogenous melanin- and hydrogen-based nano-system for RA theranostics. 2-nitroimidazole-hyaluronic acid (NI-HA) serves as a carrier to co-load melanin nanoparticles (MNPs), a hydrogen donor (AB) and indocyanine green (ICG); the construct is specifically activated within the hypoxic, mildly acidic milieu characteristic of RA (Fig. 19B). Within RA lesions, melanin affords efficient photothermal conversion (37.40 %), AB releases hydrogen for anti-inflammatory and antioxidant effects, and ICG enables NIR-II imaging to guide therapy. The platform markedly ameliorates CIA-mouse symptoms, yet controlled hydrogen release, long-term metabolism and potential toxicity remain to be systematically addressed—a key translational hurdle [62]. Chao et al. developed a bifunctional HA-PBA-TiO₂ Janus nanoparticle platform for RA treatment (Fig. 19C). The HA coating enhanced the biocompatibility and targeting ability of the nanoparticles, allowing efficient accumulation at the diseased joint site. Under 660 nm laser irradiation, the nanoparticles exhibited excellent photocatalytic water-splitting ability to produce H₂ and O₂, which alleviated oxidative stress and improved the hypoxic microenvironment in RA inflammatory sites, further improving therapeutic efficacy. Moreover, the introduction of Co and Ni enabled the nanoparticles to generate photothermal effects under NIR irradiation, precisely targeting and killing FLS cells and effectively inhibiting their abnormal proliferation, providing a promising approach for RA treatment [63].

Fig. 19.

Schematic diagram of nanomaterial design and specific mechanisms for combined therapy in RA treatment. (A) Synergistic chemotherapy/PTT/oxygen enrichment by multifunctional liposomal polydopamine nanoparticles for rheumatoid arthritis treatment. Reprinted from Ref. [61]. Copyright 2024, Elsevier. (B) Endogenous Melanin and Hydrogen-Based Specific Activated Theranostics Nanoagents: A Novel Multi-Treatment Paradigm for Rheumatoid Arthritis. Reprinted from Ref. [62]. Copyright 2024, John Wiley and Sons. (C) Hyaluronic acid modified prussian blue analogs/TiO₂ janus nanostructures through efficient charge separation to enhance photocatalytic-driven dual gas for achieve multimodal treatment of rheumatoid arthritis. Reprinted from Ref. [63]. Copyright 2024, Elsevier. (D) Photogenerated electrons from CeO₂ via upconversion of excitons to conduction band enhanced photocatalysis for Photo-Therapy of Rheumatoid arthritis. Reprinted from Ref. [64]. Copyright 2022, Elsevier. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Zhao et al. developed FT-HA-MTX NPs, a HA-decorated MOF nanoplatform for targeted RA therapy. The particles accumulate at inflamed sites via HA-CD44 recognition, simultaneously deliver photothermal/photodynamic therapy under single-wavelength laser irradiation, and employ Fenton chemistry to convert H₂O₂ into ·OH and O₂, boosting ROS cytotoxicity while relieving hypoxia. Co-loaded MTX achieves 68.28 % macrophage cytotoxicity in vitro and markedly attenuates joint swelling and inflammatory cytokine expression in AIA mice. Long-term MTX toxicity, MOF degradation kinetics, and metal-ion safety remain to be systematically assessed [20]. Li et al. developed V-USPC, a nanoplatform that targets inflamed joints through VIP receptors (Fig. 19D). CeO₂ catalytically evolves O₂ from H₂O₂ (83 % efficiency), relieving hypoxia and down-regulating HIF-1α; up-conversion nanoparticles convert NIR to UV–vis to activate CeO₂ for ‧OH production; platinum nanoparticles mediate photothermal heating (19.3 °C rise in 10 min). These components establish a virtuous cycle: O₂ overcomes hypoxic constraints on photodynamic therapy, while heat accelerates H₂O₂ diffusion and CeO₂ catalysis. In CIA mice, the arthritis index fell from 10 to 2.3, and bone density increased by 45 %, showing potent efficacy, but long-term safety requires further evaluation [64].

5.2. Synergistic SDT/gas therapy

The ROS generated by SDT and the antioxidant function of gas therapy form a dynamic balance, which enhances the killing efficiency of inflammatory cells, avoids damage to normal tissues, and significantly improves therapeutic safety. The synergistic strategy of SDT and gas therapy achieves multiple effects—ROS-mediated cell killing, antioxidant protection, immunomodulation, and microenvironmental improvement—through the multifunctional design of nanomaterials [121].

Zhou et al. constructed a copper-doped ZIF-8 nanoreactor (BMCC) co-loaded with Cu(II)-Ce⁶⁺ complexes and BSA-MnO₂ nanoparticles for synergistic SDT/CDT of RA. The system features a dual-triggered activation mechanism: under the acidic RA microenvironment, BMCC degrades to release Cu(II)-Ce⁶⁺, which is subsequently reduced by overexpressed cysteine, restoring Ce⁶⁺ fluorescence and sonosensitizing activity. This "double-insurance" strategy ensures precise SDT activation only within inflamed joints. Simultaneously, surface-coated BSA-MnO₂ reacts with H₂O₂ to generate O₂, alleviating hypoxia. Released Cu²⁺ participates in Fenton-like reactions with cysteine and H₂O₂ to yield ‧OH, enabling CDT. Combined, SDT and CDT synergistically inhibit fibroblast-like synoviocyte proliferation and improve RA symptoms. This microenvironment-responsive nanoreactor offers a targeted and safe approach for precision RA therapy [43] (Table 5) (Fig. 20).

Table 5.

Summary of current combined nanosystems for RA therapy.

Acoustic diagnosis and therapy	Photothermal therapy	Gas therapy	Nano-system	Targets	Animal model	Mechanisms	Effects	Key features	Limitations	Refs.
–	PTT	O2	MPM@Lipo	Macrophage	AIA rats	1O2↑ H2O2 and HIF-α↓ 2IL-6, IL-1β, TNF-α, and iNOS↓ CD206 and Arg-1↑P13-Akt↓	Alleviates joint swelling, suppresses inflammatory cytokine production, improves joint pathology, and reduces cartilage tissue damage.	Stimuli-responsive release; synergistic therapy.	Sub-optimal targeting efficacy.	[61]
PA	PTT	H2	MAHI NG	RASFs	CIA mice	1H2↑ ROS↓ 2IL-6, IL-1β, and TNF-α↓	Alleviates synovitis and bone erosion, improves joint smoothness, and enables clear PA visualisation of RA lesions.	Microenvironment-triggered release; synergistic therapy; endogenous, biocompatible materials.	Challenges in large-scale production processes.	[62]
–	PTT	H2	Pt-MOF@Au@QDs/PDA	HFLS-RA cell	CIA mice	1H2↑ ROS↓ 2IL-6 and TNF-α↓	Alleviates oxidative stress in RA mice, significantly mitigates joint damage, and suppresses overall arthritis severity.	High drug loading; on-demand activation; PA imaging capability; combined PTT.	Costly materials and complex synthesis; unknown long-term metabolic fate.	[54]
–	PTT	H2+O2	HA-PBA-TiO2 Janus	RAFLS	CIA mice	1H2 and O2↑ ROS↓	Reduces synovial cell proliferation, mitigates cartilage and bone destruction, and lowers arthritis index scores.	Photocatalytic dual-gas production; efficient charge separation and stability.	Synthesis process complexity.	[63]
–	PTT + PDT	O2	FT-HA-MTX NPs	Macrophage	AIA rats	1O2 and ‧OH↑ 2IL-1β and TNF-α↓	Significantly reduces joint redness and swelling, decreases pro-inflammatory cytokine levels, and improves joint structure and inflammatory symptoms.	Enhanced SDT via O2; synergistic SDT via Fenton-based ‧OH; high drug loading.	Long-term safety challenges.	[53]
–	PTT + PDT	O2	V-USPC	RAFLS	CIA mice	O2 and ‧OH↑ HIF-α and H2O2↓	Alleviates joint hypoxia, suppresses synovial cell proliferation, reduces inflammation, and inhibits bone destruction.	Microenvironment responsivity; deep-tissue therapeutic potential; autocatalytic cycle.	Long-term safety is unknown; sub-optimal energy conversion efficiency.	[64]
SDT	–	O2	BMCC NPs	RAFLS	CIA mice	O2, 1O2, and ‧OH↑	Reduces clinical joint scores, decreases joint and paw thickness, mitigates bone erosion and cartilage damage, and suppresses synovial hyperplasia.	SDT activated by weak acid and cysteine, reducing off-target toxicity; hypoxia alleviation enhances SDT efficacy.	Long-term in vivo metabolic pathway is unknown; potential biocompatibility risks remain unclear.	[43]

Fig. 20.

Schematic diagram of nanoparticle design and their therapeutic mechanisms for RA treatment based on combined therapy.

6. Conclusion and outlook

In recent years, PTT, PDT, PA, SDT, and gas therapy have shown considerable promise for RA owing to their high targeting efficiency and low systemic toxicity. During this evolution, functional nanomaterials have acted as key enablers: their unique size, surface tunability, and superior photothermal and sonosensitising properties allow precise drug delivery, enhanced bioavailability, and seamless integration of photonic, acoustic, and gas-based modalities, facilitating the shift from monotherapy to multi-mechanism combination therapy. Moreover, the electromagnetic characteristics of nanomaterials are emerging as a focal area, exemplified by Qi's fibroblast-activation-protein-targeted zinc ferrite nanoparticles that dually trigger endoplasmic-reticulum stress, inducing mitochondrial dysfunction and apoptosis, and providing the first demonstration of magnetothermal-nanocatalytic synergy for RA. Collectively, these advances not only improve efficacy and reduce adverse effects but also open entirely new technological avenues for RA management [122].

Multimodal nano-therapy has achieved landmark progress in RA, yet clinical translation remains hindered by three critical bottlenecks: First, incomplete biosafety and long-term toxicity evaluation. Most studies rely on short-term rodent data, while human long-term exposure outcomes—material accumulation, immunogenicity, and organ toxicity—remain undefined. Systematic investigation of synovium-specific toxic mechanisms is lacking, thereby hindering clinical risk assessment. Second, sub-optimal targeting accuracy and deep penetration. Thickened synovial lining and pannus act as physiological barriers, leading to sub-optimal drug accumulation. Additionally, visible/NIR-I activation suffers sharp effective-light decay in deep tissue, markedly reducing efficacy in large-joint disease and representing a major translational obstacle. Last, inadequate scalability and standardisation. Laboratory-scale syntheses often yield poor size uniformity and activity loss upon scale-up, and unified in vivo efficacy criteria are absent. Current models (mice/rats) fail to replicate human RA heterogeneity and chronic relapse, limiting clinical extrapolation.

To overcome current limitations, future efforts must target three translational pillars—precision, safety, and clinical scalability. First, with respect to targeting precision and tissue penetration, engineer smart nanocarriers that respond to multiple stimuli for inflammatory-site enrichment and integrate microneedle delivery to enhance large-joint penetration. Concurrently, develop NIR-II photosensitizers and high-penetration focused-ultrasound systems to transcend current tissue-penetration limits. Second, in terms of safety, fabricate carriers from natural biopolymers and apply surface engineering (PEGylation, biomimetic coatings) to improve biocompatibility, reduce immunogenicity, and address long-term toxicity and accumulation. Design nanocarriers responsive to RA microenvironmental cues or external triggers to enable on-demand, site-specific drug release. Such spatio-temporal precision minimises systemic leakage and off-target effects. Last, with respect to scalability and clinical translation, create high-performance nanomaterials via simple, equipment-light syntheses to improve batch uniformity and scale-up reliability. Employ AI algorithms that fuse patient imaging and immune metrics to generate personalised protocols, and deploy multi-modal imaging guidance for real-time therapy monitoring. Validate findings in 3D synovial organoids that replicate human microanatomy and in long-term primate toxicology studies focused on synovial accumulation and immune-cell interactions, thereby maximising clinical translatability.

Although multimodal nano-therapy still faces significant challenges in the path toward clinical translation, it is evident that its integrated therapeutic potential offers a concrete direction for the precision management of RA. By synergistically achieving accurate localisation, on-demand drug release, real-time monitoring, and physicochemical co-treatment, this unified strategy holds promise for conquering this complex chronic disease [123,124]. Looking forward, the deep interdisciplinary integration of materials science, imaging, artificial intelligence, and immunology should view current bottlenecks as catalysts propelling the field to new heights. Continued refinement of targeting and penetration strategies, systematic establishment of biosafety frameworks, and advancing clinically directed translational research will, we believe, enable multimodal nano-therapy to deliver safer, more effective, and personalised disease-control solutions for patients, while providing a replicable paradigm for treating other autoimmune disorders.

CRediT authorship contribution statement

Yuxin Chen: Writing – review & editing, Writing – original draft, Investigation. Yasi Deng: Investigation. Bin Li: Investigation. Yupei Yang: Investigation. Hanwen Yuan: Investigation. Huihong Duan: Investigation. Wei Wang: Supervision, Investigation, Funding acquisition. Huanghe Yu: Writing – review & editing, Supervision, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.