Hemoglobin Nanocrystals for Drugs Free, Synergistic Theranostics of Colon Tumor

Abstract The conventional approach in cancer nanomedicine involves advanced drug nanocarriers delivering preloaded therapeutics to targeted tumor sites to maximize drug efficiency. However, both cancer drugs and nanocarriers inevitably produce side effects and systemic toxicity. Herein, hemoglobin nanocrystals (HbC) as drug‐free theranostic nanoformulations with the tumor microenvironment (TME) activated diagnostic and therapeutic abilities towards colon tumors are introduced. HbC can release Fe²⁺ oxidized to Fe³⁺ in the Fenton reaction with tumor endogenous H₂O₂, concurrently with the generation of cytotoxic hydroxyl radicals (•OH) that allow for chemodynamic therapy (CDT). Furthermore, in situ‐produced Fe³⁺ reacts with colon tumor‐abundant H₂S, resulting in the production of Fe_1−xS, which provides magnetic resonance imaging (MRI) contrast and allows for NIR light‐inducible photothermal therapy (PTT). In vitro and in vivo studies revealed that HbC produced CDT towards 4T1 tumors, and MRI‐guided, synergistically enhanced combination of CDT and PTT against H₂S abundant colon tumors (CT26), with negligible toxicity towards normal tissues, enlightening HbC as highly efficient and biocompatible TME activated theranostic nanoplatform specific against colon cancer without any traditional drugs and drug carriers.