Dear Editor, Currently, the enhanced permeability and retention (EPR) effect-one of the main mechanisms through which nanomedicines 1 enter solid tumors after intravenous administration-has been mired in controversy due to its variation in different tumors 2 and species 3 (e.g., insufficient interendothelial gaps in human tumors compared with mouse models). In this study, a zeolitic imidazolate frameworks (ZIF-8) nanocarrier, to facilitate codelivery of doxorubicin (DOX) and acetazolamide (ACE), was prepared using a one-pot process and applied with ultrasound-guided percutaneous intratumoral injection. Rational design of the (DOX+ACE)@ZIF-8 considered the following facts: (a) after single-dose percutaneous F I G U R E 1 Construction and proposed mechanism of (DOX+ACE)@ZIF-8 against the hepatic in-situ tumor models. A, The preparation of metal-organic frameworks nanocarrier-based (DOX+ACE)@ZIF-8 through one-pot process. B, High tumor accumulation of (DOX+ACE)@ZIF-8 through single-dose percutaneous intratumoral injection under ultrasound guidance, followed by the cellular internalization via endocytosis pathways. At the tumor site, pH-responsive released ACE inhibits CAIX from catalyzing CO 2 to HCO 3 − and H + for "desensitizing" the cancer cells to the pH changes, thus enhancing the anticancer activity of DOX This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.