Advancing Precision: A Controllable Self-Synergistic Nanoplatform Initiating Pyroptosis-Based Immunogenic Cell Death Cascade for Targeted Tumor Therapy.

Heterogeneity of the tumor microenvironment (TME) is primarily responsible for ineffective tumor treatment and uncontrolled tumor progression. Pyroptosis-based immunogenic cell death (ICD) therapy is an ideal strategy to overcome TME heterogeneity and obtain a satisfactory antitumor effect. However, the efficiency of current pyroptosis therapeutics, which mainly depends on a single endogenous or exogenous stimulus, is limited by the intrinsic pathological features of malignant cells. Thus, it is necessary to develop a synergistic strategy with a high tumor specificity and modulability. Herein, a synergistic nanoplatform is constructed by combining a neutrophil camouflaging shell and a self-synergistic reactive oxygen species (ROS) supplier-loaded polymer. The covered neutrophil membranes endow the nanoplatform with stealthy properties and facilitate sufficient tumor accumulation. Under laser irradiation, the photosensitizer (indocyanine green) exogenously triggers ROS generation and converts the laser irradiation into heat to upregulate NAD(P)H:quinone oxidoreductase 1, which further catalyzes ß-Lapachone to self-produce sufficient endogenous ROS, resulting in amplified ICD outcomes. The results confirm that the continuously amplified ROS production not only eliminates the primary tumor but also concurrently enhances gasdermin E-mediated pyroptosis, initiates an ICD cascade, re-educates the heterogeneous TME, and promotes a systemic immune response to suppress distant tumors. Overall, this self-synergistic nanoplatform provides an efficient and durable method for redesigning the immune system for targeted tumor inhibition.

Stepwise responsive carboxymethyl chitosan-based nanoplatform for effective drug-resistant breast cancer suppression.

Efficient delivery systems for co-delivery of P-glycoprotein (P-gp) inhibitors and chemotherapeutic drugs are essential for inhibiting multi-drug resistance (MDR) breast cancers. Herein, we present a multi-functional carboxymethyl chitosan (CMC) based core-shell nanoplatform to co-deliver MDR1 gene-silenced small interfering RNA (siMDR1) and doxorubicin (DOX) for optimal combinatorial therapy. DOX is linked to CMC through a disulfide bond to model redox-responsive prodrug (CMC-DOX) as the inner core. siMDR1 is encapsulated in oligoethylenimine (OEI), which is electrostatically adsorbed on CMC-DOX as the pH-responsive sheddable shielding shell. AS1411 aptamer and GALA peptide functionalised hyaluronic acid (AHA/GHA) are provided on the surface for tumour-targeting and endo/lysosomal escape. The nanoplatform could stepwise release payloads with acid/redox triggered fashion. AHA effectively improves nanoplatform intracellular uptake and tumour accumulation. GHA facilitates cargos escape from endo/lysosomes to cytoplasm. The multi-functional nanoplatform provides 86.3 ± 2.2% siMDR1 gene silencing and significantly downregulates P-gp expression. Moreover, it ensures 55.7 ± 1.6% MCF-7/ADR cell apoptosis at a low concentration of DOX (30 µg/mL) in vitro and performs synergistic therapeutic effects suppressing tumour growth in vivo. Overall, the multi-functional CMC-based biopolymers can be efficient siRNA/drug co-delivery carriers for cancer chemotherapy.

Targeted delivery and stimulus-responsive release of anticancer drugs for efficient chemotherapy.

Chemotherapy is currently an irreplaceable strategy for cancer treatment. Doxorubicin hydrochloride (DOX) is a clinical first-line drug for cancer chemotherapy. While its efficacy for cancer treatment is greatly compromised due to invalid enrichment or serious side effects. To increase the content of intracellular targets and boost the antitumor effect of DOX, a novel biotinylated hyaluronic acid-guided dual-functionalized CaCO3-based drug delivery system (DOX@BHNP) with target specificity and acid-triggered drug-releasing capability was synthesized. The ability of the drug delivery system on enriching DOX in mitochondria and nucleus, which further cause significant tumor inhibition, were investigated to provide a more comprehensive understanding of this CaCO3-based drug delivery system. After targeted endocytosis by tumor cells, DOX could release faster in the weakly acidic lysosome, and further enrich in mitochondria and nucleus, which cause mitochondrial destruction and nuclear DNA leakage, and result in cell cycle arrest and cell apoptosis. Virtually, an effective tumor inhibition was observed in vitro and in vivo. More importantly, the batch-to-batch variation of DOX loading level in the DOX@BHNP system is negligible, and no obvious histological changes in the main organs were observed, indicating the promising application of this functionalized drug delivery system in cancer treatment.