Constructing Spatiotemporally Controllable Biocatalytic Cascade in RBC Nanovesicles for Precise Tumor Therapy Based on Reversibly Induced Glucose Oxidase-Magnetoferritin Dimers.

Chemodynamic therapy is a promising tumor treatment strategy. However, it remains a great challenge to overcome the unavoidable off-target damage to normal tissues. In this work, it is discovered that magnetoferritin (M-HFn, biomimic peroxidase) can form nanocomplexes with glucose oxidase (GOD) in the presence of glucose, thus inhibiting the enzyme activity of GOD. Interestingly, GOD&M-HFn (G-M) nanocomplexes can dissociate under near-infrared (NIR) laser, reactivating the enzyme cascade. Based on this new finding, a spatiotemporally controllable biocatalytic cascade in red blood cell (RBC) nanovesicles (G-M@RBC-A) is fabricated for precise tumor therapy, which in situ inhibits enzyme cascade between GOD and M-HFn during blood circulation and reactivates the cascade activity in tumor site by NIR laser irradiation. In RBC nanovesicles, GOD is grabbed by M-HFn to form G-M nanocomplexes in the presence of glucose, thus inhibiting the Fenton reaction and reducing side effects. However, after NIR laser irradiation, G-M nanocomplexes are spatiotemporally dissociated and the cascade activity is reactivated in the tumor site, initiating reactive oxygen species damage to cancer cells in vivo. Therefore, this work provides new insight into the fabrication of spatiotemporally controllable biocatalytic cascade for precise cancer therapy in the future.

Biomimetic magnetofluorescent ferritin nanoclusters for magnetic resonance and fluorescence-dual modal imaging and targeted tumor therapy.

Multiple imaging by combining magnetic resonance (MR) and fluorescence imaging into a single nanosystem displays distinctive merits, which is desirable for precise in vivo imaging. In this work, we proposed a new tumor-targeting dual-modal diagnosis strategy by designing and fabricating a biocompatible nano-erythrocyte and successfully delivering it into in vivo tumors. The novel nano-contrast agent (CMR) was prepared by encapsulating human heavy-chain ferritin (HFn) nanoparticles with Cy5.5 binding and mineralized iron oxide nanoparticles (Fe3O4 NPs) into erythrocyte membranes (RBCs). We demonstrated that the as-prepared CMR displayed excellent biocompatibility with low hepatotoxicity and long blood circulation time. More importantly, by functionalizing the CMR with different types of targeting moieties, the nanosystem could precisely target both subcutaneous and orthotopic tumors, and exhibited excellent MR and fluorescence dual-model imaging ability. Moreover, we demonstrated that the CMR was able to modulate the tumor microenvironment to achieve an efficient antitumor effect.

Self-activated in vivo therapeutic cascade of erythrocyte membrane-cloaked iron-mineralized enzymes.

Biomineralization of enzymes for in vivo diagnosis and treatment of diseases remain a considerable challenge, due to their severe reaction conditions and complicated physiological environment. Herein, we reported a biomimetic enzyme cascade delivery nanosystem, tumor-targeted erythrocyte membrane (EM)-cloaked iron-mineralized glucose oxidases (GOx-Fe0@EM-A) for enhancing anticancer efficacy by self-activated in vivo cascade to generate sufficient high toxic •OH at tumor site. Methods: An ultra-small Fe0 nanoparticle (Fe0NP) was anchored in the inner cavity of glucose oxidase (GOx) to form iron-mineralized glucose oxidase (GOx-Fe0) as a potential tumor therapeutic nanocatalyst. Moreover, erythrocyte membrane cloaking delivery of GOx-Fe0in vivo was designed to effectively accumulate ultra-small GOx-Fe0 at tumor site. Results: GOx-Fe0@EM-A had satisfactory biocompatibility and light-trigged release efficiency. Erythrocyte membrane cloaking of GOx-Fe0@EM-A not only prolongs blood circulation but also protects in vivo enzyme activity of GOx-Fe0; Tumor targeting of GOx-Fe0@EM-A endowed preferential accumulation at tumor site. After NIR light irradiation at tumor site, erythrocyte membrane of GOx-Fe0@EM-A was ruptured to achieve light-driven release and tumor deep penetration of ultra-small nanosize GOx-Fe0 by the photothermal effect of ICG. Then, GOx-Fe0 occurred self-activated in vivo cascade to effectively eradicate tumor by producing the highly cumulative and deeply penetrating •OH at tumor site. Conclusion: Tumor-targeted erythrocyte membrane-cloaked iron-mineralized glucose oxidase (GOx-Fe0@EM-A) exhibits a promising strategy for striking antitumor efficacy by light-driven tumor deep penetration and self-activated therapeutic cascade.

Worm-Like Biomimetic Nanoerythrocyte Carrying siRNA for Melanoma Gene Therapy.

A major challenge in siRNA vectors is developing approaches that ensure that when administered in vivo, the vectors can target their requisite site of action. This study reports a third type of nanoworm, biomimetic nanoerythrocytes for siRNA delivery, except for filomicelle and nanoworm iron-oxide particle, which is the first approach that allows for targeted siRNA delivery by a process involving red blood cell (RBC) membrane cloaking of charge-reversible polyplexes of siRNA and polycation. RBC membrane cloaking protects siRNA from RNase A degradation. Moreover, the RBC membrane-cloaked charge-reversible siRNA vector (RBC-reversible polyplex (RP)) not only stays longer in the blood circulation than that of negatively charged bovine serum albumin (BSA) spheres and positively charged BSA, but is also able to escape from late endosomes/lysosomes, to achieve effective transfection for gene knockdown. The knockdown result in vivo is remarkably consistent with that of intracellular trafficking and transfection in vitro. Due to the outstanding biocompatibility and active targeting (cRGD), the 7 mg kg-1 dose siSurvivin in RGD-RBC-RP exhibits obviously superior anticancer effects at the animal level after two weeks. Therefore, the biomimetic worm-like nanoerythrocyte charge-reversible gene vector is a new and general method for highly efficient siRNA therapy in vivo.

Light-Triggered Biomimetic Nanoerythrocyte for Tumor-Targeted Lung Metastatic Combination Therapy of Malignant Melanoma.

Red blood cell (RBC) membrane-cloaked nanoparticles, reserving the intact cell membrane structure and membrane protein, can gain excellent cell-specific functions such as long blood circulation and immune escape, providing a promising therapy nanoplatform for drug delivery. Herein, a novel RBC membrane biomimetic combination therapeutic system with tumor targeting ability is constructed by embedding bovine serum albumin (BSA) encapsulated with 1,2-diaminocyclohexane-platinum (II) (DACHPt) and indocyanine green (ICG) in the targeting peptide-modified erythrocyte membrane (R-RBC@BPtI) for enhancing tumor internalization and synergetic chemophototherapy. R-RBC@BPtI displays excellent stability and high encapsulation efficiency with multiple cores enveloped in the membrane. Benefited from the stealth functionality and targeting modification of erythrocyte membranes, R-RBC@BPtI can significantly promote tumor targeting and cellular uptake. Under the near-infrared laser stimuli, R-RBC@BPtI presents remarkable instability by singlet oxygen and heat-mediated cleavage so as to trigger effective drug release, thereby achieving deep penetration and accumulation of DACHPt and ROS in the tumor site. Consequently, R-RBC@BPtI with tumor-specific targeting ability accomplishes remarkable ablation of tumors and suppressed lung metastasis in vivo by photothermal and chemotherapy combined ablation under phototriggering. This research provides a novel strategy of targeted biomimetic nanoplatforms for combined cancer chemotherapy-phototherapy.