Protein Immobilization Inspired Lysosomal Disruption for Efficient Nuclear Drug Delivery

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Tumor cells exhibit high metabolism, creating a unique tumor microenvironment (TME).
• Enhanced lysosomal activity in tumor cells can degrade chemotherapeutics, reducing drug efficacy.
• Targeting TME and tumor cell lysosomes is crucial for improving drug delivery and cancer treatment.

Purpose of the Study:

• To develop a dual-responsive supramolecular nanomedicine for specific targeting of the TME and tumor cell lysosomes.
• To investigate the mechanism of action, including lysosomal membrane permeabilization (LMP) and subsequent cell death.
• To evaluate the efficacy and biosafety of the novel nanomedicine in vitro and in vivo.

Main Methods:

• Development of a dual-responsive supramolecular nanomedicine (FPA/DOX) inspired by protein immobilization.
• Utilizing hypoxia and acidic TME conditions to trigger benzaldehyde group exposure.
• Inducing protein covalent immobilization on lysosomal proteins, leading to LMP and drug release.
• Assessing in vitro cytotoxicity and in vivo tumor inhibition rates.

Main Results:

• FPA/DOX demonstrated specific targeting of TME and tumor cell lysosomes.
• The nanomedicine induced lysosomal membrane permeabilization (LMP) and lysosomal-dependent cell death (LDCD).
• In vitro studies showed FPA/DOX was 4.2 times more toxic than free DOX.
• In vivo studies confirmed high biosafety and a tumor inhibition rate of 95.27%.

Conclusions:

• Lysosomal disruption via protein immobilization is a novel strategy for cancer therapy.
• The developed FPA/DOX nanomedicine offers enhanced drug specificity and efficiency.
• This approach holds significant potential for future biomedical applications in oncology.