No abstract

Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug–loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti–PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.

Reactive oxygen species (ROS)-activated immunotherapy is decided by the ROS level and immunosuppressive microenvironment. This report shows the construction of indoleamine 2,3-dioxygenase (IDO) inhibitor dimers (d-ss-DO)-loaded polymer nanoparticles assembled from Ce6-tethered disulfide bond-bridged copolymers. The biomimetic polymeric nanoparticles can serve as glutathione peroxidase to deplete glutathione (GSH) and realize the dense-to-loose structure inversion (SI) arising from GSH-triggered disulfide bonds breakage, which favors d-ss-DO release and GSH-arised d-ss-DO cleavage into monomer. This sequential GSH metabolism disturbance can break the redox equilibrium and induce cell dyshomeostasis for facilitating more ROS accumulation and removing cancer stress protection in the photodynamic process. More significantly, the cleaved monomer modulates tryptophan (Trp) metabolism for blockading IDO immune escape target and liberating IDO-induced immune dampening effect, which along with massively accumulated ROS, mitigates the immunosuppressive microenvironment for potentiating systematic immune responses and increasing tumor vulnerability especially after combining with anti-PD-L1. Thus, the SIbridged sequential amino acid (i.e., GSH, Trp) metabolism disturbance brings about the largest photodynamic-evoked immunotherapeutic consequences against breast cancer and melanoma via altering the expressions of apoptosis-amino acids biosynthesis-and glycolysis/ gluconeogenesis-related genes, thus holding high potential in ROSactivated immunotherapy.