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]