Protamine-Based Nanotherapeutics for Gene Delivery to Glioblastoma Cells.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Isocitrate dehydrogenase wild-type glioblastoma is a highly aggressive, grade 4 primary brain tumor.
• Standard treatments cause severe side effects and tumor recurrence is universal.
• Nucleic acid-based therapies offer a promising alternative for cancer treatment.

Purpose of the Study:

• To explore the potential of low molecular weight protamine (LMWP) and dextran sulfate nanoparticles (NPs) as non-viral gene delivery vehicles.
• To evaluate the physicochemical properties and nucleic acid condensation capacity of the LMWP-dextran sulfate NPs.
• To assess the *in vitro* and *in vivo* efficacy and safety of these NPs for glioblastoma gene therapy.

Main Methods:

• Nanoparticles were formulated via ionic complexation of LMWP and dextran sulfate.
• Physicochemical characterization included particle size, surface charge, and morphology.
• Nucleic acid condensation ability was assessed using competitive displacement assays.
• *In vitro* studies utilized glioblastoma cell lines and 3D spheroids.
• *In vivo* efficacy and toxicity were evaluated in zebrafish models.

Main Results:

• LMWP-dextran sulfate NPs formed a homogeneous, spherical population with small size and positive surface charge.
• NPs efficiently condensed nucleic acids, maintaining their integrity even after long-term storage.
• *In vitro* and *in vivo* studies demonstrated negligible toxicity, efficient cellular uptake, and consistent protein expression.
• The NPs showed promising gene delivery capabilities in glioblastoma models.

Conclusions:

• Cationic polymeric nanoparticles composed of LMWP and dextran sulfate are effective non-viral gene delivery vehicles.
• This formulation exhibits favorable physicochemical properties and demonstrates safety and efficacy for glioblastoma treatment.
• These nanoparticles represent a promising platform for developing advanced gene therapies against aggressive brain tumors.