Chemoimmunotherapy has shown great potential to activate an immune response, but the immunosuppressive microenvironment associated with T cell exhaustion remains a challenge in cancer therapy. The proper immune‐modulatory strategy to provoke a robust immune response is to simultaneously regulate T‐cell exhaustion and infiltration. Here, a new kind of carrier‐free nanoparticle is developed to simultaneously deliver chemotherapeutic drug (doxorubicin, DOX), cytolytic peptide (melittin, MPI), and anti‐TOX small interfering RNA (thymocyte selection‐associated high mobility group box protein, TOX) using a fluorinated prodrug strategy. In this way, the enhanced immunogenic cell death (ICD) induced by the combination of DOX and MPI can act as “offense” signaling to increase CD8+ T‐cell infiltration, while the decreased TOX expression interfered with siTOX can serve as “defense” signaling to mitigate CD8+ T‐cell exhaustion. As a result, the integration of DOX, MPI, and siTOX in such a bifunctional system produced a potent antitumor immune response in liver cancer and metastasis, making it a promising delivery platform and effective strategy for converting “cold” tumors into “hot” ones.

Nano-based immunotherapy of therapeutic biomolecules is attractive but tremendously hampered by the poor delivery efficiency. This study reports a novel delivery system of fluorinated-coordinative-epigallocatechin gallate (EGCG), referring as FEGCG/Zn, through the integration of fluorination and zinc ions (Zn 2+ ) into EGCG. The robust therapeutics of FEGCG/Zn are measured in terms of the regulating effect on programmed cell death ligand 1 (PD-L1), the effective delivery of diverse biomolecules, and the hitchhiking ability using living cells. Taking small interfering RNA of PD-L1 (siPD-L1) and erythrocytes as an example, the fabricated biomimetic system achieves excellent siPD-L1 delivery and further improves siPD-L1 accumulation in tumors. Finally, the combination of FEGCG/Zn and siPD-L1 promotes antitumor immunotherapy through alleviation of T cells exhaustion by regulating PD-L1 expression in tumor cells. The results demonstrate that FEGCG/Zn substantially regulates PD-L1 expression and improves immune-biomolecule delivery by forming biomimetic nanoassemblies, offering a versatile platform for cancer immunotherapy.

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Purpose: Melittin (MPI) is a potential anticancer peptide due to its abilities of antitumor and immunomodulatory functions. Epigallocatechin-3-Ogallate (EGCG), a major extract of green tea, has shown great affinity for various types of biological molecules, especially for peptide/protein drugs. The aim of this study is to prepare a fluoro- nanoparticle (NP) formed by self-assembly of fluorinated EGCG (FEGCG) and MPI, and evaluate the effect of fluorine modification on MPI delivery and their synergistic antitumor effect. Methods: Characterization of FEGCG@MPI NPs was determined by dynamic light scattering (DLS) and transmission electron microscope (TEM). Biology functions of FEGCG@MPI NPs were detected by hemolysis effect, cytotoxicity, apoptosis, cellular uptake with confocal microscopy and flow cytometry. The protein expression levels of Bcl-2/Bax, IRF, STATT-1, P-STAT-1, and PD-L1 were determined via western blotting. A transwell assay and wound healing assay were used to detect the cell migration and invasion. The antitumor efficacy of FEGCG@MPI NPs was demonstrated in a subcutaneous tumor model. Results: Fluoro-nanoparticles could be formed by self-assembly of FEGCG and MPI, and fluorine modification on EGCG could ameliorate the side effect and delivery of MPI. The promoted therapeutics of FEGCG@MPI NPs could be achieved by regulating PD-L1 and apoptosis signaling, which might involve pathways of IRF, STAT-1/pSTAT-1, PD-L1, Bcl-2, and Bax in vitro . Moreover, FEGCG@MPI NPs could significantly inhibit the growth of tumor in vivo . Conclusions: FEGCG@MPI NPs may offer a potential platform and promising strategy in cancer therapy.

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