To engineer patient‐derived cells into therapy‐purposed biologics is a promising solution to realize personalized treatments. Without using gene‐editing technology, a live cell‐typed therapeutic is engineered for tumor treatment by artificially reprogramming macrophages with hyaluronic acid‐decorated superparamagnetic iron oxide nanoparticles (HIONs). This nanoparticle‐assisted cell‐reprogramming strategy demonstrates profound advantages, due to the combined contributions from the biological regulation of HIONs and the intrinsic nature of macrophages. Firstly, the reprogrammed macrophages present a substantial improvement in their innate capabilities, such as more effective tumor targeting and more efficient generation of bioactive components (e.g., reactive oxygen species, bioactive cytokines) to suppress tumor growth. Furthermore, this cell therapeutic exhibits cytostatic/proapoptotic effects specific to cancer cells. Secondly, HIONs enable macrophages more resistant to the intratumoral immunosuppressive environment. Thirdly, the macrophages are endowed with a strong ability to prime in situ protumoral M2 macrophages into antitumor M1 phenotype in a paracrine‐like manner. Consequently, a synergistic tumor‐inhibition effect is achieved. This study shows that engineering nanomaterial‐reprogrammed live cells as therapeutic biologics may be a more preferable option to the commonly used approaches where nanomaterials are administrated to induce bioresponse of certain cells in vivo. A live cell‐typed therapeutic is engineered for tumor treatment by reprogramming macrophages with HION nanoparticles. The advantage of this ex vivo cell‐reprogramming strategy is evidenced by cancer‐cell‐specific toxicity, more efficient production of bioactive components, stronger resistance against intratumoral immunosuppression, and favorable ability to prime in situ protumoral M2 macrophages into antitumor M1 phenotype in a paracrine‐like manner.