Hypoxia
at the tumor site limits the therapeutic effects
of photodynamic
therapy (PDT) in oral squamous cell carcinoma (OSCC), which is an
oxygen-consumption process. Inhibiting cellular oxygen consumption
and reducing cellular ATP production are expected to enhance PDT.
In this study, we designed and constructed dandelion-like size-shrinkable
nanoparticles for tumor-targeted delivery of hypoxia regulator resveratrol
(RES) and photodynamic agent chlorine e6 (CE6). Both drugs were co-encapsulated
in small-sized micelles modified with EGFR targeting ligand GE11,
which was further conjugated on hyaluronic nanogel (NG) to afford
RC-GMN. After targeted accumulation in tumors mediated by GE11 and
enhanced penetration and retention (EPR) effects, RC-GMN was degraded
by hyaluronidase (HAase) and resulted in small-sized micelles, allowing
for deep penetration and dual-receptor-mediated cellular internalization.
Resveratrol inhibited cellular oxygen consumption and provided sufficient
oxygen for PDT, which consequently activated PDT to produce reactive
oxygen species (ROS). Notably, we found that autophagy was overactivated
in PDT, which was further strengthened by the hypoxia regulator resveratrol,
elevating autophagic cell death. The synergistic effects of resveratrol
and CE6 promoted autophagic cell death and apoptosis in the enhanced
PDT, resulting in stronger antitumor effects in the orthotopic OSCC
model. Therefore, the facilitated delivery of hypoxia regulator enhanced
PDT efficacy by elevating oxygen content in tumor cells and inducing
autophagic cell death and apoptosis, which offers an alternative strategy
for enhancing the PDT effects against OSCC.