On-call Mito-Firefighter: Dual-activated nanoparticles based on carboxymethyl chitosan/β-cyclodextrin to achieve...

Indocyanine green (ICG) demonstrates both photodynamic therapy (PDT) and photothermal therapy (PTT) capabilities but faces challenges including rapid blood clearance, insufficient ROS production, and molecular chaperone-induced thermotolerance. However, highly efficient synchronous targeting delivery of photosensitizer and sensitizer to cancer cells remains a giant challenge due to their significantly different physicochemical properties. To address these limitations, we developed a dual-responsive nano-platform, TCS-βCD@CLRP/PEI-SS@ICG-NPs (I&C-NPs), designed for ICG and chloramphenicol (CLRP) co-delivery and cascade synergetic anti-tumor effect through mitochondrial destruction/photothermal therapy/photodynamic therapy (Mito destruction/PTT/PDT). Mitochondrial-targeted "pocket" cyclodextrin-grafted carboxymethyl chitosan (TCS-βCD) and biodegradable disulfide-grafted polyethyleneimine (PEI-SS) were designed and synthesized. Mitochondrial respiration consumes oxygen in cells like "oxygen consumption for fire", while CLRP, the "fire extinguisher", can inhibit mitochondrial respiration and reduce oxygen consumption. Through multiple intermolecular forces, PEI-SS and TCS-βCD encapsulated ICG with 71.05 % efficiency and CLRP with 78.18 % efficiency, forming I&C-NPs exhibiting 123.5 nm in size and exhibiting a zeta potential of +7.8 mV. These nanoparticles functioned as "On-call firefighter", targeting mitochondria through dual responsiveness to elevated glutathione (GSH) in the tumor microenvironment (TME) and laser-induced photothermal heating. The system achieved GSH-/laser-activated drug release efficiency of >80 % and efficient cascade synergetic anti-tumor efficacy: (1) I&C-NPs target and disrupt the mitochondria of tumor cells, and CLRP acts as a PDT sensitizer to minimize oxygen consumption. (2) The PDT effect can be amplified, generating large amounts of ROS (1.69-fold compared to free ICG) in vivo and showing a reduction of HIF-1α. (3) The production of ROS disrupts heat shock proteins and down-regulates HSP 70 protein expression, decreasing tumor tolerance to hyperthermia and resulting in robust photothermal conversion efficiency. Consequently, GSH-/laser-activated mitochondria-oriented I&C-NPs could co-deliver ICG and CLRP, achieving the cascade synergetic anti-tumor effect of Mito destruction/PTT/PDT with the tumor inhibitory rate > 77 %.