Acid/Enzyme-Triggered Size Shrinkage and Charge Reversal Micelles for Precision Nucleus-Targeted Cancer Treatment

The efficacy of cancer treatment is often hindered by the difficulty of delivering therapeutic agents directly to the cell nucleus, a critical site of action for many anticancer drugs. To overcome this challenge, we developed adaptive micelles with size- and charge-modulation capabilities, specifically designed for precision nucleus-targeted cancer therapy. These micelles, composed of DOX-loaded TPGS 3350 -FRRGPKKKRKV(DMMA)-DOX (TFP(D)D), exhibit a stable negative surface charge (−2.16 ± 0.28 mV) and an optimal particle size (129.2 ± 1.9 nm) under physiological conditions, which minimizes protein adsorption and ensures prolonged circulation. Upon encountering the acidic pH and cathepsin B overexpression characteristic of the tumor microenvironment, the micelles undergo rapid transformation, reducing their size and switching to a positive surface charge. This dynamic adaptation enhances tumor tissue penetration, lysosomal escape, and efficient nucleus targeting. Preclinical animal studies demonstrated that TFPD(D)D micelles exhibit superior antitumor efficacy and a favorable safety profile compared to conventional delivery systems. These findings highlight the potential of adaptive micelles as a transformative platform for overcoming biological barriers in drug delivery and advancing the development of more effective cancer therapies.