Injectable Tumor‐Cell‐Mimicking Topology Accelerates the Mechanical Reprogramming of Adipocytes via the Nucleus for Enhanced Metabolic Adaptation to Obesity

ABSTRACT Tumor microenvironmental mechanical cues modulate tumor‐stroma interactions, including the overgrowth of certain types of stroma and the invasive transition of cancer cells. However, certain types of mechanical cues and the functional roles of tumor microenvironments remain poorly defined. Here, we identify cell topology as a mechanical cue driving adipocyte reprogramming: topological complexity inspired by cancer cells modulates adipocyte reprogramming efficiency, and the high‐roughness topology fabricated using highly invasive mesenchymal‐like cancer cells exerts a significantly superior regulatory effect to that of low‐roughness, less invasive epithelial‐like cancer cells. Using cell‐templated biomineralization, we decouple topological cues from other tumorigenic factors, fabricating tumor‐mimicking substrates and injectable microparticles. Substrates convert mature adipocytes into mesenchymal stem cell‐like cells, offering regenerative medicine resources; the tumor‐mimicking microparticles (TMMs) reprogram adipose pads in situ, achieving local fat reprogramming, body weight loss, and enhanced metabolic adaptation, paving a new tumor cell‐inspired mechanotherapy way towards obesity in animals. Mechanistically, we demonstrate that tumor‐mimicking topology induces nuclear mechanical remodeling and enhances nuclear transport of transcription factors, eventually modulating adipocyte reprogramming. Overall, rooted in this discovery, we present a proof‐of‐concept tumor‐inspired therapy wherein TMMs not only reprogram local adipose tissue characteristics but also improves insulin sensitivity in obese mice.