The group of Prof. Zhang Na and Prof. Liu Yongjun from the School of Pharmaceutical Sciences of Shandong University has made new progress in localized controlled release macrophage drug delivery systems to enhance tumor efficacy, and published in the Acta Pharmaceutica Sinica B (SCI Q1, Impact Factor: 14.7) entitled “Localized light-triggered release macrophage cytopharmaceuticals containing O-nitrobenzyl group for enhanced solid tumor cell-chemotherapy”. PhD candidate Liu Jinhu of Class 2023 and Master candidate Yang Han of Class 2019 are the first authors. Prof. Liu Yongjun is the corresponding author of the paper. The School of Pharmaceutical Sciences of Shandong University is the first author unit and the only corresponding author unit. Prof. Zhang Na and other partners in the research group provided important help for this study.

Living cell-based drug delivery systems have attracted extensive attention in recent years, in which drugs or drug-loaded nanoparticles are loaded with living cells ex vivo, displaying great promise in targeted drug delivery in terms of natural targeting, superior biocompatibility, prolonged circulation time, and flexible morphology. Natural cells including red blood cells, immune cells (T cells, macrophages, neutrophils, natural killer cells, etc.), and stem cells have all been used in carrier cells of living cell-based drug delivery systems. Compared with other cells, macrophages have the ability of tumor tendency, phagocytosis and killing, antigen presentation, and secretion of cytokines to regulate the immune microenvironment, and are the carrier cell types with great development potential in living cell-based drug delivery systems. However, controlling drug release at the disease site while maintaining macrophage viability and exerting their immunotherapeutic effect is still a challenge.

Fig 1 Schematic illustration of the preparation process and effective mechanism of localized light-triggered release macrophage drug delivery systems

Herein, the amphiphilic block copolymers with ultraviolet (UV)-responsive o-nitrobenzyl groups were synthesized and co-loaded with the multi-target tyrosine kinase inhibitor sorafenib (SF), macrophages polarize drug IMD-0354 (IMD) and upconverting nanoparticle (UCNP) to prepare the nanomedicine (USIP), which was then taken up by macrophages in vitro. The localized light-triggered release macrophage drug delivery system (USIP@M) was successfully prepared, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. UCNPs converted near-infrared light with strong penetrability and high safety into UV light, which promoted the photoresponsive depolymerization of block copolymers and production of exosomes from USIP@M, accelerated drug efflux and maintained the activity of macrophages. IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the antitumor effect of macrophages, enhance T cell immunity, and alleviate the immunosuppressive state of TME. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage drug delivery system that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors.

In recent years, the group of Prof. Zhang Na and Prof. Liu Yongjun has made a series of research achievements in the direction of tumor immune combination therapy and successively developed drug delivery systems based on polarized macrophages (Nanomicro Lett, 2020, 13, 6), nano-cages of reshaping the tumor immune microenvironment (ACS Nano, 2022, 16, 4263-4277), dual-conversion in-situ self-assembly vaccines (Chem Eng J, 2023, 454, 140190), autologous tumor vaccines (Biomaterials, 2023, 297, 122104), nano-inducers of reshaping the tumor-lymph node immune microenvironment (Nat Commun, 2023, 14, 2248), and nano-edited macrophage cytopharmaceutical (Nat Commun, 2024, 15, 8203), etc. The above research work has been strongly supported by the National Natural Science Foundation of China, the Excellent Youth Fund of Shandong Province, and the Qilu Young Scholars Program at Shandong University.