Organoids, self-organizing, three-dimensional (3D) multicellular structures derived from tissues or stem cells, offer physiologically relevant models for studying human development and disease. Compared to conventional two-dimensional (2D) cell cultures and animal models, organoids more accurately recapitulate the architecture and function of human organs. Among the critical microenvironmental cues influencing organoid behavior, hypoxia and multilineage communication are particularly important for guiding cell fate, tissue organization, and pathological modeling. Hypoxia, primarily regulated by hypoxia-inducible factors (HIFs), modulates cellular proliferation, differentiation, metabolism, and gene expression, making it a key component in disease modeling. Similarly, multilineage communication, facilitated by intercellular interactions and extracellular matrix (ECM) remodeling, enhances organoid complexity and immunological relevance. This review explores the dynamic interplay between hypoxia and multilineage signaling in 3D organoid-based disease models, emphasizing recent advances in engineering hypoxic niches and co-culture systems to improve preclinical research fidelity. We also discuss their translational implications for drug screening, regenerative medicine, and precision therapies, while highlighting current challenges and future opportunities. By integrating biophysical, biochemical, and computational approaches, next-generation organoid models may be further optimized for translational research and therapeutic innovation.

Arthritic diseases are a significant global health challenge, highlighting the urgent need for innovative therapeutic strategies. Extracellular vesicles (EVs) have emerged as promising candidates for treating various intractable diseases. This review explores the therapeutic potential of engineered EVs in joint diseases, particularly in comparison to their parental stem cells. Recent research underscores the efficacy of EVs in treating joint diseases, especially Osteoarthritis (OA). We discuss EV engineering strategies aimed at overcoming the limitations of natural EVs. Data from preclinical trials, clinical studies, and in vitro and in vivo reports are analyzed to evaluate the effectiveness of EVs in treating joint conditions. In addition to their role in intercellular communication, EVs influence various biological processes crucial for bone remodeling, cartilage regeneration, immunomodulation, and inflammation control. EVs are rich in vital biomolecules such as proteins, microRNAs (miRNA), lipids, and nucleic acids, which enhance their therapeutic potential compared to parental stem cells. This understanding is key to developing targeted and effective engineered EVs for OA and other joint diseases. A comprehensive grasp of EV engineering and underlying mechanisms will pave the way for novel and efficient therapies for arthritic diseases and related conditions.This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Nanotechnology Approaches to Biology > Cells at the Nanoscale Biology‐Inspired Nanomaterials > Peptide‐Based Structures