CXCL10-coronated thermosensitive "stealth" liposomes for sequential chemoimmunotherapy in melanoma.

Area of Science:

• Nanomedicine
• Immunotherapy
• Drug Delivery

Background:

• Liposome-protein corona interactions impede clinical use due to rapid clearance and immune cell uptake.
• Developing stealth nanocarriers is crucial for effective drug delivery and therapeutic outcomes.

Purpose of the Study:

• To engineer stealth-like nanocarriers by decorating thermosensitive liposomes (TSLs) with CXCL10 and oridonin (ORD/CXCL10/TSLs).
• To evaluate the efficacy of ORD/CXCL10/TSLs in overcoming biological barriers, targeting tumors, and enhancing anti-cancer immunity.

Main Methods:

• Coronation of TSLs with therapeutic protein CXCL10 to create CXCL10/TSLs.
• Decoration of CXCL10/TSLs with hyaluronic acid conjugated oridonin (ORD/CXCL10/TSLs).
• Assessment of leukocyte capture, tumor targeting, macrophage polarization, immune cell expansion, and synergistic effects with anti-PD-L1 in a metastatic melanoma mouse model.

Main Results:

• ORD/CXCL10/TSLs reduced leukocyte capture and enabled specific tumor targeting.
• Hyperthermia-activated ORD/CXCL10/TSLs induced a sustained CXCL10 inflammatory loop, promoting M1-like macrophage polarization and expanding tumor-infiltrating natural killer cells.
• Oridonin synergized with CXCL10 to inhibit PI3K/AKT and Raf/MEK signaling, suppressing tumor cell migration.
• ORD/CXCL10/TSLs combined with anti-PD-L1 antibody demonstrated potent synergy, inducing immunological memory and controlling metastatic spread.

Conclusions:

• ORD/CXCL10/TSLs represent a multifunctional nanomedicine platform overcoming biological barriers for enhanced cancer immunotherapy.
• This approach effectively reprograms the tumor microenvironment, synergizes with checkpoint inhibitors, and controls metastatic disease.