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]