Biomimetic Engineering of a Scavenger‐Free Nitric Oxide‐Generating/Delivering System to Enhance Radiation Therapy

Nitric oxide (NO) is a potent tumor‐cell radiosensitizer but it can be readily scavenged by hemoglobin (Hb) in vivo. A biomimetic incubator that can generate and deliver NO in a scavenger (Hb)‐free environment to enhance its radiosensitizing effect to maximize its efficacy in radiotherapy is proposed. This NO incubator comprises a poly(lactic‐co‐glycolic acid) (PLGA) hollow microsphere (HM) that contains an NO donor (NONOate) and a surfactant molecule (sodium caprate, SC) in its aqueous core. In acidic tumorous environments, the PLGA shell of the HM allows the penetration of protons from the outside, activating the hydrolytic cleavage of NONOate, spontaneously generating NO bubbles, which are immediately trapped/stabilized by SC. The SC‐stabilized NO bubbles in the HM are then squeezed through the spaces of its PLGA matrices by the elevated internal pressure. Upon leaving the HM, the entrapped NO molecules may passively diffuse through their SC‐stabilized/protected layer gradually to the tumor site, having a long‐lasting radiosensitizing effect and inhibiting tumor growth. The entire process of NO generation and delivery is conducted in a scavenger (Hb)‐free environment, mimicking the development of young ovoviviparous fish inside their mothers' bodies in the absence of predators before birth.     

Hemoglobin Nanocrystals for Drugs Free,Synergistic Theranostics of Colon Tumor (Small 8/2023)

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.