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

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Lung cancer exhibits high mortality, necessitating novel therapeutic strategies.
• Ferroptosis therapy shows promise but is limited by insufficient reactive oxygen species (ROS) and poor drug accumulation.
• Targeted delivery to lung lesions is crucial for effective cancer treatment.

Purpose of the Study:

• To develop an inhalable nano-platform for enhanced lung cancer ferroptosis therapy.
• To investigate the role of calcium (Ca2+)-burst-centered endoplasmic reticulum (ER) stress in augmenting ferroptosis.
• To improve drug accumulation and therapeutic efficacy in lung cancer.

Main Methods:

• Construction of a biomineralized liposome (LDM) co-loaded with dihydroartemisinin (DHA) and pH-responsive calcium phosphate (CaP).
• Evaluation of nebulization properties and lung lesion drug accumulation compared to intravenous injection.
• Assessment of DHA-mediated ROS production, CaP-induced Ca2+ bursts, ER stress, and ferroptosis induction.
• Investigation of the Ca2+ burst-ER stress-ferroptosis cycle in an orthotropic lung tumor murine model.

Main Results:

• Inhalable LDM exhibited excellent nebulization and 6.80-fold higher lung lesion drug accumulation than intravenous injection.
• DHA induced ROS production via Fenton-like reactions, while CaP degradation triggered Ca2+ bursts and ER stress.
• The sequential Ca2+ bursts, ER stress, and subsequent mitochondrial dysfunction amplified ROS and lipid peroxidation, driving ferroptosis.
• LDM demonstrated significant lung retention and potent antitumor activity in vivo.

Conclusions:

• The developed inhalable LDM is a promising nanoplatform for nebulization-based pulmonary delivery in lung cancer treatment.
• Ca2+-burst-centered ER stress significantly enhances ferroptosis, offering a novel therapeutic approach.
• This strategy effectively overcomes limitations of traditional ferroptosis therapy by improving drug delivery and therapeutic outcomes.