Two types of pH-responsive and photo-crosslinked polymersomes were self-assembled using two distinct block copolymers (BCP-A or BCP-D) employing the pH switch technique, as outlined in prior studies (details in Supplementary Information (SI)). The main difference between Psomes A and Psomes D is the membrane permeability. Psomes D present a more hydrophobic block, resulting in a more impermeable membrane in the physiological environment compared to Psomes A. The different membrane permeability and better swelling properties of protonated Psomes membrane for both Psomes A and D are exemplified in the environment of 10 mM NaCl during a pH titration experiment validated by DLS (Fig- ). The starting point of swelling for Psomes D is in the range of pH 6.5 to lower pH values, whereas Psomes A start swelling at pH 7.5 to lower pH values. Briefly, BCP-A (mPEG45-b-P(DEAEMA-co-DMIBMA)) and BCP-D (mPEG45-b-P(nBMA-co-DEAEMA-co-DMIBMA)) employed in this study were synthesized through atom transfer radical polymerization (Table -S2, Figure ). Previously, enzyme-loaded Psomes A have shown broad applications in the field of therapeutic nanoreactors or artificial organelles. These nanostructures feature a semi-permeable membrane at pH 6.5, demonstrating enzyme stability, enzyme retention, and, in certain instances, enzyme activity regulation. However, our goal here is the controlled release of an anticancer drug, requiring a nano-compartment (Psomes D) that undergoes selective permeability in the antitumoral environment, allowing enhanced selectivity by increasing drug concentration in tumor cells and/or minimizing exposure in normal host tissues. To achieve this, BCP-A underwent a slight modification by substituting the pH-responsive monomer 2-(N,N´-diethylamino)ethyl methacrylate (DEAEMA) with the monomer n-butyl methacrylate (nBMA), resulting in BCP-D. This modification leads to the formation of permeable vesicles, Psomes D, in an environment proximal to the tumor, featuring a more hydrophobic membrane with a lower starting point of swelling at acidic pH (Figure ). With Psomes D it facilitates loading of a hydrophobic drug such as CU (details in SI, Table -S2), higher loading efficiency and controlled release by the antitumor environment.