Cascade-Responsive Hierarchical Nanosystems for Multisite Specific Drug Exposure and Boosted Chemoimmunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Combination therapy requires precise drug delivery to distinct targets, a challenge for current nanosystems.
• Biological barriers in the tumor microenvironment (TME) hinder effective treatment.
• Developing multifunctional nanocarriers is crucial for overcoming these limitations.

Purpose of the Study:

• To develop a cascade-responsive hierarchical nanosystem for spatially programmed delivery of anti-PD-L1 antibody and paclitaxel.
• To overcome biological barriers and enhance chemoimmunotherapy efficacy.
• To provide a promising nano-platform for safe and efficient combination cancer therapy.

Main Methods:

• Fabrication of hierarchical nanoparticles (MPH-NP@A) with pH-sensitive HA-ace-PTX(SH) prodrugs and MMP-9-responsive shells.
• Incorporation of anti-PD-L1 antibody (αPD-L1) for targeted release in the TME.
• Sequential release of αPD-L1 and paclitaxel (PTX) for synergistic effects in vitro and in vivo.

Main Results:

• MPH-NP@A demonstrated pH and MMP-9 responsiveness, enabling sequential drug release.
• The released αPD-L1 synergized with intracellular PTX, inducing immunogenic cell death (ICD).
• Significant tumor inhibition, enhanced cytotoxic T lymphocytes infiltration, and suppressed immune escape were observed in vivo.

Conclusions:

• The developed MPH-NP@A nano-platform enables precise, spatially programmed delivery of multiple drugs.
• This approach effectively boosts chemoimmunotherapy by combining direct tumor killing with immune system modulation.
• The nano-platform shows significant potential for safe and efficient combination cancer treatment.