ROS are highly reactive ions and free radicals, including superoxide (O₂⁻), hydroxyl radical (·OH), hypochlorite ion (OCl⁻), hydrogen peroxide (H₂O₂), and monoclinic oxygen (¹O₂) [34,88]. ROS play a crucial role in physiological functions, including the regulation of protein function, production of multiple hormones, modulation of cell signaling, mediation of inflammation, and elimination of pathogens. In general, low levels of ROS regulate cell signaling pathways and promote cell proliferation [89]. However, excessive ROS can disrupt normal signal transduction and homeostasis [90]. Based on the elevated levels of ROS specific to certain diseases, polymeric nanocarriers with distinct ROS-responsive properties may enhance targeted drug delivery for the treatment of these conditions [91]. To address the problem that the dense extracellular matrix of cartilage is poorly targeted and rapidly cleared from the cartilage surface, which prevents NP penetration and requires repetitive high-dose administration within the joint cavity, Wu et al. proposed the use of the ROS-responsive material poly(ethylene glycol diacrylate) (PEGDA)-1,2-ethylenedithiol (EDT) copolymer (PEGDA-EDT) and reduced graphene oxide (rGO) as graphene-based nanomaterials to prepare a smart ROS-responsive poly (lactic acid) (PLA)/PEGDA-EDT@rGO-fucoxanthin (PPGF) nanofibrous membrane as a DDS for OA therapy. PPGF nanofibrous membranes were prepared by introducing PEGDA-EDT as a ROS-responsive motif, rGO as a drug carrier, and fucoxanthin (Fx) as an antioxidant and anti-inflammatory agent in PLA to achieve ROS-responsiveness and long-term drug release for OA therapy. The novel nanofibrous membrane DDS could “turn on” in response to excessive ROS, prolonging the residence time of Fx in the joint cavity, promoting effective drug concentration, and improving the therapeutic efficiency of OA [71]. Inspired by oxidative stress in the pathogenesis of OA, Jiang et al. first demonstrated the antioxidant capacity of the small molecule compound oltipraz (OL) on IL-1β-treated chondrocytes. Then, a functional ROS-responsive nanocarrier, i.e., mesoporous silica NPs (MSNs) modified with methoxy polyethylene glycol-thioketal (TK) and loaded with OL, was constructed (Figure 5a). In this study, by constructing a new type of nanocarrier, the antioxidant can be brought into chondrocytes, and the drug can be intelligently released in a high-ROS environment [72]. Zhang et al. reported an innovative ROS-responsive therapeutic polymer NP capable of loading hydrophobic drugs and self-reporting the payload release upon ROS stimulation. The NPs consist of an amphiphilic block copolymer composed of PEG and an oxidatively responsive hydrophobic block containing pendant phenylboronic pinacol ester groups and a small portion of a 1,8-naphthimide dye. Since the naphthimide dye is covalently coupled to the polymer, it is possible to fluorescently track the polymer carrier inside the cell [73]. Wu et al. synthesized and assembled a hydrogen peroxide (H₂O₂, which belongs to the ROS)-sensitive nanomicelle loaded with the anti-inflammatory drug dexamethasone (DEX) and the cartilage differentiation factor chondrocyte-derived photoproduced protein-1 (CDMP-1). This low-toxicity, ROS-responsive NP (DLNP) capable of eliminating joint inflammation and inducing cartilage repair was constructed. H₂O₂ was used as a positive control, and the NPs had -SeSe- groups as the ROS-responsive component, with DEX and CDMP-1 as the main pharmacophore. The drug-carrying NPs were delivered directly to the arthritic lesions by intra-articular injection. Using the high concentration of oxygen radicals at the arthritic lesion, -SeSe- breakage and slow release of DEX and CDMP-1 were observed. The results showed that the drug-loaded micelles effectively inhibited the proliferation of activated macrophages, induced macrophage apoptosis, and had anti-inflammatory effects and led to the differentiation of BMSCs to chondrocytes [74]. Shen et al. developed a multifunctional ROS-activated therapeutic polymer NP capable of loading hydrophobic drugs and self-reporting the payload release upon ROS stimulation. The NPs consisted of a Cy5.5-modified cartilage-targeting peptide (CAP, DWRVIIPPRPSA) and a PEG-modified oxidative-responsive TK ligand hydrophobic block containing black hole quencher 3 (BHQ-3) as a quencher for Cy5.5, which was then encapsulated with DEX to form the TKCP@DEX NPs. TKCP@DEX NPs specifically targeted articular cartilage via CAP and responded to high levels of ROS due to high levels of ROS in inflamed tissues leading to sulfhydryl bond breakage, resulting in the gradual breakdown of the polymer and release of Cy5.5 and the drug (Figure 5b). The results show that the nanoprobes can be intelligently “switched on” in response to excessive ROS and “switched off” in normal joints. Especially for cartilage, TKCP@DEX can effectively respond to ROS and slow-release DEX to significantly reduce cartilage damage in OA joints. An in vivo experiment was conducted to evaluate the therapeutic effect of TKCP@DEX on OA. By observing the macroscopic appearance and scores of the cartilaginous femoral condyles at 2 and 4 weeks after treatment, the results showed that the TKCP@DEX group reduced the damage by 65% and 57.78%, respectively, which demonstrated its effective restorative effect in the treatment of OA (Figure 5c) [75]. Tang et al. reported an innovative self-reporting drug delivery platform based on ROS-responsive random copolymers (P1) capable of visualizing drug release kinetics through activation of an integrated fluorophore. P1 is synthesized by co-polymerization of boronic acid pinacol, PEG, and naphthalene dicarbonyl imide monomers, which endow ROS sensitivity, hydrophilicity, and fluorescence signals, respectively [76]. ROS-responsive materials have been the focus of numerous studies as one of the triggering drug release mechanisms for responsive polymeric DDSs. ROS are overexpressed at high concentrations at many disease sites. The differences between normal and pathological tissues make ROS-responsive delivery systems with great potential for many disease applications [92].