The development of nanotheranostics for precision imaging-guided
regulated cell death-mediated synergistic tumor therapy is still challenging.
Herein, a novel multifunctional nanotheranostic agent, iRGD-coated
maleimide-poly(ethylene glycol)-poly(lactic acid/glycolic acid)-encapsulated
hydrophobic gold nanocages (AuNCs) and hydrophilic epigallocatechin
gallate (EGCG) (PAuE) is developed for multispectral optoacoustic
tomography (MSOT)-guided photothermal therapy (PTT) and chemotherapy.
The portions of necroptotic and apoptotic tumor cells were 52.9 and
5.4%, respectively, at 6 h post-incubation after the AuNC-induced
mild PTT treatment, whereas they became 14.0 and 46.1% after 24 h,
suggesting that the switch of the cell death pathway is a time-dependent
process. Mild PTT facilitated the release of EGCG which induces the
downregulation of hypoxia-inducible factor-1 (HIF-1α) expression
to enhance apoptosis at a later stage, realizing a remarkable tumor
growth inhibition in vivo. Moreover, RNA sequence analyses provided
insights into the significant changes in genes related to the cross-talk
between necroptosis and apoptosis pathways via PAuE upon laser irradiation.
In addition, the biodistribution and metabolic pathways of PAuE have
been successfully revealed by 3D MSOT. Taken together, this strategy
of first combination of EGCG and AuNC-based photothermal agent via
triggering necroptosis/apoptosis to downregulate HIF-1α expression
in a tumor environment provides a new insight into anti-cancer therapy.