Safe and Localized Lentiviral Gene Delivery via Injectable Mesoporous Scaffolds for Potent Antitumor Immunity

Area of Science:

• Biomedical Engineering
• Immunology
• Gene Therapy

Background:

• Lentiviral vectors enable sustained gene expression but face safety challenges like systemic spread and insertional mutagenesis.
• Targeted delivery to immune cells is crucial for effective in vivo gene therapy.

Purpose of the Study:

• To develop a safe and efficient method for in vivo targeted gene delivery to dendritic cells (DCs) using a spatially confined lentiviral system.
• To overcome the limitations of conventional lentiviral vectors for in vivo applications.

Main Methods:

• A modular, injectable scaffold was engineered by functionalizing mesoporous silica with lentiviral vectors encoding tumor antigens and granulocyte-macrophage colony-stimulating factor.
• The scaffold self-assembles to recruit DCs, facilitating localized transduction and minimizing systemic vector dissemination.

Main Results:

• The scaffold successfully achieved localized transduction of DCs, restricting genome integration to recruited immune cells.
• This approach led to prolonged antigen expression and enhanced MHC-I-mediated antigen presentation.
• In melanoma models, the method induced robust antigen-specific CD8+ T-cell responses, improved effector memory generation, and boosted antitumor immunity.
• Combination with immune checkpoint blockade further enhanced therapeutic efficacy.

Conclusions:

• This spatially confined lentiviral gene delivery system offers a safe and versatile platform for in vivo gene therapy.
• The strategy holds significant potential for treating cancer, infectious diseases, and autoimmune disorders.