Universal diseased-site targeting via glycolysis-driven lactic acid gradient

Area of Science:

• Biomedical Engineering
• Drug Delivery
• Metabolic Engineering

Background:

• Targeted delivery of protein therapeutics is crucial for effective treatment but remains a significant challenge.
• Pathological conditions often exhibit altered metabolic states, such as elevated glycolysis, leading to extracellular acidification.
• Current targeting strategies have limitations in scale and applicability.

Purpose of the Study:

• To develop a universal strategy for targeted delivery of protein therapeutics.
• To leverage the acidic microenvironment of pathological tissues for navigational cues.
• To improve therapeutic efficacy and reduce systemic toxicity of biologics.

Main Methods:

• Encapsulation of therapeutic proteins within pH-responsive polymer shells.
• Utilizing dynamic charge modulation of nanocapsules in response to pH gradients.
• Employing a receptor-independent, long-range targeting approach.
• Testing the platform in in vivo models of cancer, chronic inflammation, and acute injury.

Main Results:

• Nanocapsules selectively accumulated at diseased sites in cancer, inflammation, and injury models.
• The pH-responsive shells enabled navigation towards acidic pathological environments.
• Enhanced therapeutic efficacy was observed with reduced systemic toxicity.
• Demonstrated long-range, receptor-independent targeting capabilities.

Conclusions:

• The lactate acid gradient-mediated targeting (LaGET) platform offers a novel paradigm for targeted protein delivery.
• Leveraging metabolic signatures like extracellular acidification provides a universal targeting strategy.
• This approach has broad potential for treating various diseases requiring protein therapeutics.