Lung-Selective Immune Reprogramming via In Situ Red Blood Cell Hitchhiking Nanoparticles.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Drug Delivery

Background:

• Nanoparticle (NP) drug delivery faces challenges with premature clearance and poor organ targeting.
• Current red blood cell (RBC) hitchhiking methods require complex ex vivo procedures, hindering clinical application.

Purpose of the Study:

• To develop an in situ RBC hitchhiking strategy for enhanced nanoparticle circulation and organ-selective delivery.
• To investigate the potential of this platform for targeted immune reprogramming in lung diseases and cancer metastasis.

Main Methods:

• Surface functionalization of nanoparticles with polyphenols to promote spontaneous attachment to RBCs in vivo (i-Bind strategy).
• Evaluation of NP-RBC binding stability under flowing whole blood conditions.
• Assessment of biodistribution, lung targeting efficiency, and immune cell subset targeting in healthy and diseased mouse models.
• Therapeutic efficacy testing using a STING agonist in a melanoma lung metastasis model.

Main Results:

• i-Bind nanoparticles demonstrated stable and enhanced hitchhiking on RBCs in situ.
• A >20-fold increase in lung-to-liver deposition ratio was observed compared to unmodified NPs.
• Pathology-dependent targeting of specific lung immune cell subsets (cDC2s, neutrophils, cDC1s) was achieved.
• Treatment with i-Bind NPs carrying a STING agonist significantly inhibited lung metastasis progression.

Conclusions:

• The i-Bind strategy offers a simplified and effective approach for in situ RBC hitchhiking, improving nanoparticle circulation and lung targeting.
• This platform enables precise delivery to distinct lung immune cell populations, facilitating immune microenvironment reprogramming.
• i-Bind holds significant promise for advancing organ-selective drug delivery and immunotherapy for lung diseases and metastatic cancers.