Inflammation-responsive nanoparticles suppress lymphatic clearance for prolonged arthritis therapy.

The clearance of nanomedicine in inflamed joints has been accelerated due to the increased lymph angiogenesis and lymph flow in arthritic sites. To maximize the therapeutic efficacy for rheumatoid arthritis (RA), it is necessary to facilitate targeted delivery and extended drug retention in inflamed synovium simultaneously. In general, nanosized particles are more likely to achieve prolonged circulation and targeted delivery. While drug carriers with larger dimension might be more beneficial for extending drug retention. To balance the conflicting requirements, an inflammation-responsive shape transformable nanoparticle, comprised of amyloid ß-derived KLVFF peptide and polysialic acid (PSA), coupled with therapeutic agent dexamethasone (Dex) via an acid-sensitive linker, was fabricated and termed as Dex-KLVFF-PSA (DKPNPs). Under physiological condition, DKPNPs can keep stable nanosized morphology, and PSA shell could endow DKPNPs with long circulation and active targeting to arthritic sites. While in inflamed joints, acidic pH-triggered Dex dissociation or macrophages-induced specific binding with PSA would induce the re-assembly of DKPNPs from nanoparticles to nanofibers. Our results reveal that intravenously injected DKPNPs display prolonged in vivo circulation and preferential distribution in inflamed joints, where DKPNPs undergo shape transition to fibrous structures, leading to declined lymphatic clearance and prolonged efficacy. Overall, our dual-stimulus responsive transformable nanoparticle offers an intelligent solution to achieve enhanced therapeutic efficacy in RA.

Inflammation-homing "living drug depot" for efficient arthritis treatment.

Delivering therapeutic agents efficiently to inflamed joints remains an intractable problem in rheumatoid arthritis (RA) treatment due to the complicated physiological barriers. Circulating monocytes could selectively migrate to inflamed sites and differentiate into resident macrophages to aggravate RA. Therefore, a drug carrier that can be specifically internalized by circulating monocytes and switch monocytes into anti-inflammatory phenotype when reaching inflamed sites, might bypass the in vivo physiological barriers and achieve efficient RA therapy. Herein, we design a dextran sulfate (DS) functionalized nanoparticle (ZDNP) to selectively deliver anti-inflammatory agent dexamethasone (Dex) to circulating monocytes via the scavenger receptors on monocytes. Monocytes engulfing drug-loaded ZDNP could subsequently home to arthritic joints and act as a "living drug depot" to combat RA. Results revealed that ZDNP could be preferentially internalized by circulating monocytes when intravenously administrated in vivo. In a rat arthritic model, we found that circulating monocytes remarkably facilitated drug distribution and retention in inflamed joints. Moreover, monocytes engulfing drug-loaded nanoparticles exhibited favorable anti-inflammatory ability and M2-biased differentiation. Our work offers a facile approach to achieve site-directed anti-inflammatory therapy by taking advantage of the inflammation-homing ability of circulating monocytes. STATEMENT OF SIGNIFICANCE: Circulating monocytes can migrate to inflamed sites and then differentiate into macrophages to aggravate arthritis. Therefore, a drug carrier that can be specifically internalized by circulating monocytes and switch monocytes into anti-inflammatory phenotype when reaching inflamed sites may achieve efficient arthritis therapy. Here, we designed a monocyte-targeting nanoparticle (ZDNP) to selectively deliver anti-inflammatory Dex to circulating monocytes. When injected intravenously, ZDNP was effectively internalized by circulating monocytes via a scavenger receptor and subsequently was transported to arthritic joints, where monocytes engulfing the drug-loaded nanoparticles could switch to an anti-inflammatory phenotype to inhibit arthritis progress. We provide detailed evidence about the in vivo fate of ZDNP and unravel how monocytes act as a "living drug depot" to achieve site-directed arthritis therapy.

Injectable Micelle-Incorporated Hydrogels for the Localized Chemo-Immunotherapy of Breast Tumors.

Although immune checkpoint blockade (ICB) holds potential for the treatment of various tumors, a considerable proportion of patients show a limited response to ICB therapy due to the low immunogenicity of a variety of tumors. It has been shown that some chemotherapeutics can turn low-immunogenic tumors into immunogenic phenotypes by inducing a cascade of immune responses. In this paper, we synthesized an injectable micelle-incorporated hydrogel, which was able to sequentially release the chemotherapeutic gemcitabine (GEM) and the hydrophobic indoleamine 2, 3-dioxygenase inhibitor, d-1-methyltryptophan (d-1MT) at tumor sites. The hydrogel was formed via the thiol-ene click reaction between the thiolated chondroitin sulfate and the micelle formed by amphiphilic methacrylated Pluronic F127, in which hydrophobic d-1MT was encapsulated in the core of the F127 micelles and the hydrophilic GEM was dispersed in the hydrogel network. The successive release of chemotherapeutics and immune checkpoint inhibitors at tumor tissues will first promote the infiltration of cytotoxic T lymphocytes and subsequently induce a robust antitumor immune response, ultimately exerting a synergetic therapeutic efficacy. In a 4T1 tumor-bearing mice model, our results showed that the combination of chemotherapy and immunotherapy through the micelle-incorporated hydrogel triggered an effective antitumor immune response and inhibited tumor metastasis to the lung. Our results highlight the potential of the injectable micelle-incorporated hydrogel for the localized chemo-immunotherapy in the treatment of breast tumors.

Dual-Stimuli Responsive Polymeric Micelles for the Effective Treatment of Rheumatoid Arthritis.

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.