H-shaped miktobrush copolymer nanoassembly facilitates ultrafast nucleus delivery for multi-stimuli-cooperative tumour suppression

Abstract The potencies of antitumour compounds are often compromised by their restricted subcellular delivery to nucleus, although a variety of smart vehicles have been extensively designed to release drug in endocytic organelles. A major challenge remains in exploring the nanocarriers with robust and spatiotemporal responsiveness for yielding efficient subcellular targeting due to tumour heterogeneity. Herein, we show an H-shaped miktobrush copolymer nanoassembly (NAs) with ultrafast nucleus delivery for multi-stimuli-cooperative suppression against primary and metastatic triple-negative breast cancer (TNBC) models. The micellar NAs display acidity- and glutathione-responsive drug releases through the protonation and disulfide-bridge cleavage, which are further amplified by irreversible photo-controlled oxidation and phase transition in a ratiometric manner, leading to rapid morphological destruction and ultrafast cytoplasmic translocation into the nucleus from the lysosomes in a few minutes. These micellar NAs thus show a distinctly enhanced cooperativity of photochemotherapeutic efficacy through considerable apoptotic behavior, potently suppressing subcutaneous and orthotopic TNBC models, together with enhanced survival rates. Moreover, these NAs yield preferable anti-metastatic efficacy through the inhibition of metastasis-relevant proteins as compared to chemotherapy and surgical resection. These results provide the insight into multi-stimuli-responsive polymers for ultrafast nucleus delivery against aggressive tumours.