Knee osteoarthritis (OA) is one of the most common causes of pain and disability, affecting over 500 million people worldwide. The tremendous socio-economic burden caused by OA is expected to further increase due to rising life expectancy and obesity. Current therapeutic approaches are limited to pain management or knee arthroplasty, but no disease-modifying or regenerative treatment is available. ENCANTO will address this major unmet clinical need by clinically introducing a combined ATMP for the biological reconstruction of the degenerated joint facet in patellofemoral OA (PFOA). This tissue-engineered cartilage (N-TEC), based on autologous nasal chondrocytes and a collagen membrane, was previously successfully used for focal cartilage lesions. The central part of ENCANTO is an international, blinded, multicenter, prospective randomized controlled phase II trial to clinically assess the efficacy of N-TEC for the treatment of PFOA. Patients’ samples will be analyzed to retrospectively identify PFOA molecular endotypes and associated biomarker signatures with the most successful clinical outcome after N-TEC implantation, to predictively select responders to therapy. To achieve these aims ENCANTO brings together tissue engineers with practice in ATMPs, knee surgery and rehabilitation specialists, research institutes experienced in regulatory affairs, health economics and ATMP development, excellent scientists involved in the assessment of OA endotypes, and patients’ representatives. SMEs from the consortium will develop a road map towards commercial exploitation, including centralized marketing authorization. After demonstrating efficacy for PFOA, N-TEC will be considered for other forms of OA in different joints. ENCANTO will thus introduce the first disease-modifying therapy for cartilage degeneration, enable mobility and social gain for a large patient group and play a pivotal role in strengthening Europe's position in delivering regenerative medicine solutions.