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.
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