Inhalable Biomimetic Protein Corona-Mediated Nanoreactor for Self-Amplified Lung Adenocarcinoma Ferroptosis Therapy

Abstract

Ferroptosis therapy by catalyzing the Fenton reaction has emerged as a promising tumor elimination strategy for lung adenocarcinoma (ADC). However, the unsatisfactory Fenton reaction efficiency, strong intracellular antioxidant system, and insufficient lung drug accumulation limits the ferroptosis therapeutic effect. To address these issues, an inhalable nanoreactor was proposed by spontaneously adsorbing biomimetic protein corona (PC) composed of matrix metalloproteinase 2 responsive gelatin and glutamate (Glu) on the surface of cationic nanostructured lipid carriers (NLC) core loaded with ferrocene (Fc) and fluvastatin. The prepared Fc-NLC­(F)@PC could be nebulized into lung lesions with 2.6 times higher drug accumulation and boost lipid peroxide production by 3.2 times to enhance ferroptosis therapy. Mechanically, fluvastatin was proved to inhibit monocarboxylic acid transporter 4 mediated lactate efflux, inducing tumor acidosis to boost Fc-catalyzing reactive oxygen species production, while the extracellular elevating Glu concentration was found to inhibit xCT (system Xc –) functions and further collapse the tumor antioxidant system by glutathione synthesis suppression. Mitochondrial dysfunction and cell membrane damage were involved in the nanoreactor-driven ferroptotic cell death process. The enhanced antitumor effects by combination of tumor acidosis and antioxidant system collapse were confirmed in an orthotopic lung ADC tumor model. Overall, the proposed nanoreactor highlights the pulmonary delivery approach for local lung ADC treatment and underscores the great potential of ferroptosis therapy.

Photocatalytic Generation of Hydrogen Radical (H⋅) with GSH for Photodynamic Therapy

“…The LPO accumulation was positively dependent on the TAF concentration (Figure S32). It is known that excessive LPO could induce damage of membrane structure [34c] . Commercial fluo‐3‐acetoxymethyl (Fluo‐3 AM) was utilized as a Ca 2+ probe to assess the intracellular osmotic pressure.…”

Inhalable Biomineralized Liposomes for Cyclic Ca2+-Burst-Centered Endoplasmic Reticulum Stress Enhanced Lung Cancer Ferroptosis Therapy

“…These tendencies were still maintained after 24-h incubation (Figure S10). The highest intracellular Ca 2+ levels of the LDM group might be attributed to the cyclic Ca 2+ burst, which may be induced by the synergy effect of CaP degradation and the formation of ferroptotic pores …”

“…The highest intracellular Ca 2+ levels of the LDM group might be attributed to the cyclic Ca 2+ burst, which may be induced by the synergy effect of CaP degradation and the formation of ferroptotic pores. 52 Thus, the next step is to confirm the formation of ferroptotic pores, which was not only the result of the ferroptosis-induced phospholipid bilayer disruption but also the trigger of the second Ca 2+ burst. 53,54 The cell membrane was first stained by the DIO probe (Figure 4E).…”

Amplified Fenton-Based Oxidative Stress Utilizing Ultraviolet Upconversion Luminescence-Fueled Nanoreactors for Apoptosis-Strengthened Ferroptosis Anticancer Therapy

“…Under laser-on conditions, the UFCL+L and UFL+L demonstrated a high ratio of green to red fluorescence intensities, indicating a depolarization from J-aggregates to J-monomers due to the ferroptosis-induced ΔΨm reduction, which is less exhibited in the nonlaser condition or cisplatin treatment. Furthermore, the appearance of cell swelling and the rough surface of the cells are the signature of ferroptosis. − To clarify the cell surface characteristics, we applied 3D atomic force microscopy (3D-AFM) for nontreated (PBS) and treated (UFCL+L) 4T1 cells. The 3D-AFM images (Figure C) of UFCL+L treatment showed the appearance of circular protrusions (blue arrows) in addition to the doubled cell height (Figure D) and a rougher cell surface (Figure E) compared to the control sample (PBS).…”