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Cartilage-targeting peptide-modified dual-drug delivery nanoplatform with NIR laser response for osteoarthritis
Song Xue1, Xiaojun Zhou2, Weilin Sang1
1Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Abstract:
Cartilage-targeting delivery of therapeutic agents is still an effective strategy for osteoarthritis (OA) therapy. Recently, scavenging for reactive oxygen species (ROS) and activating autophagy have been increasingly reported to treat OA effectively. In this study, we designed, for the first time, a dual-drug delivery system based on metal organic framework (MOF)-decorated mesoporous polydopamine (MPDA) which composed of rapamycin (Rap) loaded into the mesopores and bilirubin (Br) loaded onto the shell of MOF. The collagen II-targeting peptide (WYRGRL) was then conjugated on the surface of above nanocarrier to develop a cartilage-targeting dual-drug delivery nanoplatform (RB@MPMW). Our results indicated the sequential release of two agents from RB@MPMW could be achieved via near-infrared (NIR) laser irritation. Briefly, the rapid release of Br from the MOF shell exhibited excellent ROS scavenging ability and anti-apoptosis effects, however responsively reduced autophagy activity, to a certain extent. Meanwhile, following the NIR irradiation, Rap was rapidly released from MPDA core and further enhanced autophagy activation and chondrocyte protection. RB@MPMW continuously phosphorylated AMPK and further rescued mitochondrial energy metabolism of chondrocytes following IL-1β stimulation via activating SIRT1-PGC-1α signaling pathway. Additionally, the cartilage-targeting property of peptide-modified nanocarrier could be monitored via Magnetic Resonance (MR) and IVIS imaging. More significantly, RB@MPMW effectively delayed cartilage degeneration in ACLT rat model. Overall, our findings indicated that the as-prepared dual-drug delivery nanoplatform exerted potent anti-inflammation and anti-apoptotic effects, rescued energy metabolism of chondrocytes in vitro and prevented cartilage degeneration in vivo, which thereby showed positive performance for OA therapy.
Insights
This study introduces a novel dual-drug delivery system for osteoarthritis therapy. The nanoplatform targets cartilage, releases therapeutic agents sequentially, and shows promise in treating osteoarthritis in animal models.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Drug Delivery Systems
Background:
- Osteoarthritis (OA) therapy benefits from cartilage-targeting drug delivery.
- Reactive oxygen species (ROS) scavenging and autophagy activation are emerging OA treatment strategies.
Purpose of the Study:
- To design and evaluate a novel cartilage-targeting dual-drug delivery nanoplatform for osteoarthritis therapy.
- To investigate the synergistic effects of sequential drug release for enhanced chondrocyte protection and cartilage preservation.
Main Methods:
- Fabrication of a metal-organic framework (MOF)-decorated mesoporous polydopamine (MPDA) nanocarrier loaded with rapamycin (Rap) and bilirubin (Br).
- Conjugation of a collagen II-targeting peptide (WYRGRL) for cartilage targeting, creating the RB@MPMW nanoplatform.
- Evaluation of sequential drug release via near-infrared (NIR) laser irradiation, assessing ROS scavenging, autophagy modulation, and chondrocyte protection in vitro.
- In vivo assessment of cartilage degeneration in an ACLT rat model using MR and IVIS imaging.
Main Results:
- The RB@MPMW nanoplatform demonstrated sequential release of Br and Rap upon NIR irradiation.
- Bilirubin (Br) exhibited ROS scavenging and anti-apoptotic effects, while rapamycin (Rap) enhanced autophagy and chondrocyte protection.
- The nanoplatform rescued mitochondrial energy metabolism in chondrocytes via the SIRT1-PGC-1α pathway.
- Cartilage targeting was confirmed by imaging, and the nanoplatform significantly delayed cartilage degeneration in vivo.
Conclusions:
- The developed cartilage-targeting dual-drug delivery nanoplatform (RB@MPMW) shows significant potential for osteoarthritis therapy.
- Sequential release of ROS scavengers and autophagy activators offers a synergistic approach to combat OA.
- The nanoplatform effectively protects chondrocytes and prevents cartilage degeneration, highlighting its therapeutic efficacy.
