Cascade-Responsive Hierarchical Nanosystems for Multisite Specific Drug Exposure and Boosted Chemoimmunotherapy
Junmei Zhang1, Yuanyuan Zhang1, Bingbing Zhao1
1Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 210009, China.
Abstract:
The precise delivery of multiple drugs to their distinct destinations plays a significant role in safe and efficient combination therapy; however, it is highly challenging to simultaneously realize the targets and overcome the intricate biological hindrances using an all-in-one nanosystem. Herein, a cascade-responsive hierarchical nanosystem containing checkpoint inhibitor anti-PD-L1 antibody (αPD-L1) and paclitaxel (PTX) is developed for spatially programed delivery of multiple drugs and simultaneously overcoming biological pathway barriers. The hierarchical nanoparticles (MPH-NP@A) are composed of pH-sensitive hyaluronic acid-acetal-PTX prodrugs (HA-ace-PTX(SH)) chaperoned by αPD-L1 and metalloproteinase-9 (MMP-9)-responsive outer shells, which could be fast cleaved to release αPD-L1 in the tumor microenvironment (TME). The released αPD-L1 sequentially synergizes with PTX released in the cytoplasm for boosted chemoimmunotherapy due to direct killing of PTX and intensified immune responses through immunogenic cell death (ICD) as well as suppression of immune escape by blocking the PD-1/PD-L1 axis. The in vitro and in vivo studies demonstrate that MPH-NP@A evokes distinct ICD, enhanced cytotoxic T lymphocytes infiltration, as well as significant tumor inhibition, thus providing a promising therapeutic nano-platform for safe and efficient combination therapy.
Insights
This study introduces a novel nanocarrier for targeted cancer therapy, delivering anti-PD-L1 and paclitaxel to enhance chemoimmunotherapy. The system effectively inhibits tumor growth by combining drug delivery with immune system activation.
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.
