Viral glycoprotein-mimicking peptide-functionalized micelles promote drug delivery to diseased chondrocytes for osteoarthritis alleviation.

Osteoarthritis (OA) affects a large population worldwide, causing chronic pain, functional decline, and increased personal and societal medical costs. A major challenge in developing disease-modifying OA drugs (DMOADs) is the inefficient delivery to diseased chondrocytes. Here we synthesize a viral glycoprotein-mimicking peptide (CMP) containing a type II collagen-adhesive motif and a matrix metalloproteinase-13-activated cell-penetrating peptide sequence. The CMP peptide was conjugated to small-sized micelles loaded with the model drug IOX4, enabling the micelles to adhere to cartilage and chondrocyte surfaces through collagen binding and achieve proteinase-induced selective uptake by diseased chondrocytes. In an OA mouse model, our micelles demonstrated prolonged joint retention and exhibited a higher uptake by diseased chondrocytes compared with unmodified micelles and normal chondrocytes, respectively. In both OA mice and a clinically relevant OA sheep model, our system maintained metabolic homeostasis in cartilage, attenuating OA pathological changes and improving symptoms without causing additional toxicity. These findings suggest that our nanoformulation is a promising DMOAD candidate and provides an efficient delivery strategy for other potential DMOADs targeting intracellular sites of diseased chondrocytes.