Ligand-Modified Erythrocyte Membrane-Cloaked Metal-Organic Framework Nanoparticles for Targeted Antitumor Therapy

Systemic chemotherapy for treating tumors often leads to serious systemic side effects and affects patient compliance. Although the emerging technology of drug delivery systems (DDSs) can deliver the required cargo to tumor sites, DDSs are limited due to insufficient targeting ability or deficient pharmacokinetics. Herein, we assembled a novel targeting DDS for precision tumor therapy by applying a tumor-targeting polypeptide cyclic RGD (cRGD)-modified erythrocyte membrane (eM-cRGD) cloaked on zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) with encapsulated doxorubicin (DOX). For a mass ratio of ZIF-8:DOX = 1:1, the loading capacity was up to 49%. The nanoscale-sized targeting DDS promoted NP accumulation in tumor tissues via enhanced permeability and retention (EPR) effects, and the NPs actively targeted ligands and were then transferred to endosomes. The pH-sensitive carriers released higher DOX levels under the low pH mimicking that of a tumor microenvironment and tumor intracellular organelles, allowing enhanced inhibition of cancer cell growth. The cumulative release rate of DOX from DOX@ZIF-8 NPs reached 82.8% at 48 h in acidic conditions of pH = 5.0, while the cumulative release rate of DOX from the DOX@ZIF-8 NPs reached only 24.92% at pH = 7.4. The internalization of the DDS was approximately 44.35% that of the unmodified DDS by immune cells, as confirmed by flow cytometry. In vivo studies verified that the RGD-modified DDS had the ability to prolong blood circulation (t(1/2) = 6.81 h), enhancing the tumor-specific accumulation of NPs by means of the integrin alpha v beta 3 receptor-mediated pathway, which was further valuated in mice bearing human cervical cancer (HeLa) cells, and yielding a significant antitumor effect; the tumor inhibition rate was as high as 85.46%. Under the same conditions, the blood circulation half-life of the unmodified DDS was only 3.22 h, and the tumor inhibition rate of free DOX was 81.34%. Moreover, the RGD modified with a carrier could achieve a satisfactory chemotherapeutic effect while minimizing side effects. In summary, our novel targeting DDS could contribute to the development of intelligent DDSs for tumor precision therapy.