Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments.

The nontargeted distribution and uncontrolled in vivo release of drugs impede their efficacy in the treatment of rheumatoid arthritis (RA). Delivering drugs to arthritic joints and releasing drugs on demand are a feasible solution to achieve the effective treatment of RA. In this paper, we report a facile method to assemble dual-stimuli responsive polymeric micelles from polyethylene glycol–phenylboric acid–triglycerol monostearate (PEG–PBA–TGMS, PPT) conjugates with the aim of delivering dexamethasone (Dex) to arthritic joints and controlling the release of Dex by inflammatory stimuli. We show that the release of Dex from the PPT micelles is accelerated in response to acidic pH and overexpressed matrix metalloproteinases. In an adjuvant-induced arthritis model, the PPT micelles preferentially accumulate in arthritic joints and show an excellent therapeutic efficacy after being intravenously administrated. Our results highlight the potential of the dual stimuli-responsive micelles as a promising therapeutic option for the effective treatment of inflammatory diseases.

An extracellular matrix-mimicking hydrogel is developed consisting of a hyaluronan-derived component with anti-inflammatory activity, and a gelatin-derived component offering adhesion sites for cell anchorage. The in situ-forming hyaluronan-gelatin (HA-GEL) hydrogel displays a sponge-like microporous morphology. Also, HA-GEL shows a rapid swelling pattern reaching maximum weight swelling ratio within 10 min, while at the equilibrium state, fully swollen hydrogels display an exceedingly high water content with ≈2000% of the dry gel weight. Under typical 2D cell culture conditions, murine 3T3 fibroblasts adhere to, and proliferate on top of the HA-GEL substrates, which demonstrate that HA-GEL provides a favorable microenvironment for cell survival, adhesion, and proliferation. In vivo healing study further demonstrates HA-GEL as a viable and effective treatment option to improve the healing outcome of full thickness wounds in diabetic mice by effectively depleting the inflammatory chemokine monocyte chemoattractant protein-1 in the wound bed.

Localized delivery, comparing to systemic drug administration, offers a unique alternative to enhance efficacy, lower dosage, and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests. Herein, a localized drug delivery platform (“plum‒pudding” structure) with controlled release and long-acting features is developed through an injectable hydrogel (“pudding”) crosslinked via self-assembled triblock polymeric micelles (“plum”) to help reduce renal interstitial fibrosis. This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice. Following a single injection, local treatments containing either anti-inflammatory small molecule celastrol or anti-TGF β antibody effectively minimize inflammation while alleviating fibrosis via inhibiting NF- κ B signaling pathway or neutralizing TGF- β 1 locally. Importantly, the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity, which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis.