Cytotoxic T lymphocyte (CTL) eliminates abnormal cells through target recognition-triggered intracellular toxin delivery. Chimeric antigen receptor T-cell improves cancer cell recognition of CTL, but its effectiveness and safety in solid tumor treatment are still hampered by poor tumor infiltration, suppressive tumor microenvironment, and severe on-target off-tumor toxicity. Given the functionality and challenges of CTL in cancer therapy, herein, a CTL-inspired nanovesicle (MPV) with a cell membrane-derived shell and a methylene blue (MB) and cisplatin (Pt) loaded gelatin nanogel core is created. The MPV generates contrast for tumor photoacoustic imaging, and produces hyperthermia upon laser irradiation, enabling photothermal imaging and deep tumor penetration. Meanwhile, it releases MB and Pt, and then delivers them into the cytosol of cancer cells, which process can be visualized by imaging the recovery of MB-derived fluorescence. The localized hyperthermia, photodynamic therapy, and chemotherapy together kill 4T1 breast cancer cells effectively, resulting in primary tumor regression and 97% inhibition of pulmonary metastasis, without significant toxicity to the animals. Taken together, the MPV shows tumor-specific and stimuli-triggered intracellular toxin delivery with advantages in traceable accumulation and activation, high tumor penetration, and triple combination therapy, and thus can be an effective nanomedicine for combating metastatic breast cancer.

Lung metastasis is challenging in patients with triple‐negative breast cancer (TNBC). Surgery is always not available due to the dissemination of metastatic foci and most drugs are powerless because of poor retention at metastatic sites. TNBC cells generate an inflamed microenvironment and overexpress adhesive molecules to promote invasion and colonization. Herein, “walking dead” TNBC cells are developed through conjugating anti‐PD‐1 (programmed death protein 1 inhibitor) and doxorubicin (DOX)‐loaded liposomes onto cell corpses for temporal chemo‐immunotherapy against lung metastasis. The walking dead TNBC cells maintain plenary tumor antigens to conduct vaccination effects. Anti‐PD‐1 antibodies are conjugated to cell corpses via reduction‐activated linker, and DOX‐loaded liposomes are attached by maleimide–thiol coupling. This anchor strategy enables rapid release of anti‐PD‐1 upon reduction conditions while long‐lasting release of DOX at inflamed metastatic sites. The walking dead TNBC cells improve pulmonary accumulation and local retention of drugs, reprogram the lung microenvironment through damage‐associated molecular patterns (DAMPs) and PD‐1 blockade, and prolong overall survival of lung metastatic 4T1 and EMT6‐bearing mice. Taking advantage of the walking dead TNBC cells for pulmonary preferred delivery of chemotherapeutics and checkpoint inhibitors, this study suggests an alternative treatment option of chemo‐immunotherapy to augment the efficacy against lung metastasis.

The authors confirm that the PI for this paper is Rongsheng Zhao and that he had direct clinical responsibility for patients included in the study investigating the patients' willingness on individualized medication of high-dose methotrexate.

Drug delivery strategies possessing selectivity for cancer cells are eagerly needed in therapy of metastatic breast cancer. In this study, the chemotherapeutic agent, docetaxel (DTX), is conjugated onto heparan sulfate (HS). Aspirin (ASP), which has the activity of anti-metastasis and enhancing T cells infiltration in tumors, is encapsulated into the HS-DTX micelle. Then the cationic polyethyleneimine (PEI)-polyethylene glycol (PEG) copolymer binds to HS via electrostatic force, forming the ASP-loaded HS-DTX micelle (AHD)/PEI-PEG nanocomplex (PAHD). PAHD displays long circulation behavior in blood due to the PEG shell. Under the tumor microenvironment with weakly acidic pH, PEI-PEG separates from AHD, and the free cationic PEI-PEG facilitates the cellular uptake of AHD by increasing permeability of cell membranes. Then the overexpressed heparanase degrades HS, releasing ASP and DTX. PAHD shows specific toxicity toward tumor cells but not normal cells, with advanced activity of inhibiting tumor growth and lung metastasis in 4T1 tumor-bearing mice. The number of CD8 + T cells in tumor tissues is also increased. Therefore, PAHD can become an efficient drug delivery system for breast cancer treatment.

Chemotherapy is among the limited choices approved for the treatment of hepatocellular carcinoma (HCC) at intermediate and advanced stages. Preferential and prolonged drug exposure in diseased sites is required to maximize the therapeutic index of the drug. Here, we report an injectable supramolecular peptide hydrogel as an intraperitoneal depot for localized and sustained release of triptolide for the treatment of orthotopic HCC. We chose peptide amphiphile C16-GNNQQNYKD-OH-based nanofibers as gelators and carriers for triptolide. Sustained triptolide release from the hydrogel was achieved over 14 days in vitro, with higher accumulation in and cytotoxicity against human HCC Bel-7402 in comparison with L-02 fetal hepatocytes. After intraperitoneal injection, the hydrogel showed prolonged retention over 13 days and preferential accumulation in the liver, realizing HCC growth inhibition by 99.7 ± 0.1% and animal median survival extension from 19 to 43 days, without causing noticeable pathological changes in the major organs. These results demonstrate that injectable peptide hydrogel can be a potential carrier for localized chemotherapy of HCC.

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes. Through metabolic engineering, bioorthogonal groups can be tagged onto cell membranes, which selectively attach to cargos with paired groups via bioorthogonal reactions. Due to its simplicity, high efficiency, and specificity, bioorthogonal chemistry has demonstrated great application potential in drug delivery. On the one hand, bioorthogonal reactions improve therapeutic agent delivery to target sites, overcoming off-target distribution. On the other hand, nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions, providing approaches to developing multi-functional drug delivery systems (DDSs). In this review, we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups. We then highlight recent breakthroughs in developing active targeting DDSs to tumors, immune systems, or bacteria by bioorthogonal chemistry, as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs (biomimetic DDSs, cell-based DDSs, bacteria-based and phage-based DDSs) and hydrogels. Finally, we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery. We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.

The therapy of triple‐negative breast cancer (TNBC) relies on chemotherapy basing on cytotoxic agents, including paclitaxel (PTX). Unfortunately, PTX will facilitate the invasion of cancer cells and the formation of metastases. To counteract pro‐metastasis of PTX in TNBC therapy, in this work, calcitriol (CTL) is delivered along with PTX by a dual‐pH‐sensitive micelle. The PTX/CTL‐co‐loaded dual‐pH‐sensitive micelle (PCDM) can switch its surface charge from negative to positive at the tumor tissue and release PTX and CTL inside the lysosomes because of the structure change of the polymers composing PCDM under the acidic condition. This property makes PCDM able to escape from mononuclear‐phagocyte system clearance and easy to enter tumor cells. PCDM efficiently suppresses the 4T1 primary tumor growth in mice and inhibits lung metastasis, due to downregulation of matrix metalloproteinase‐9 and BCL‐2 levels, upregulation of E‐cadherin level, and counteracting the PTX‐induced elevation of C‐C motif chemokine ligand 2 (CCL2) and Ly6C+ monocytes levels by CTL. PCDM shows good biocompatibility without promoting the serum calcium level. Therefore, the combination of PTX and CTL based on this pH‐sensitive micelle is promising for the TNBC treatment.

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