Acid-switchable nanoparticles induce self-adaptive aggregation for enhancing antitumor immunity of natural killer cells

Deficiency of natural killer(NK)cells shows a significant impact on tumor progression and failure of immunotherapy.It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment.Unfortunately,mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors,thus declining antitumor efficiency.Herein,we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15(IL-15).The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction,which provides a new methodology to trigger aggregation.It shows self-adaptive size-enlargement upon acidity,thus improving drug retention in tumor to over 120 h.The diameter of agglomerates is increased and drug release is effectively promoted following reduced p H values.The nanoparticles activate both NK cell and CD8+T cell immunity in vivo.It significantly suppresses CT26 tumor in immune-deficient BALB/c mice,and the efficiency is further improved in immunocompetent mice,indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity.The approach reported here provides an innovative strategy to improve drug retention in tumors,which will enhance cancer immunotherapy by boosting NK cells.

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

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.

Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma

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 by99.7 ± 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.

Tumor microenvironment-responsive docetaxel-loaded micelle combats metastatic breast cancer

Efficient tumor-targeting drug delivery systems are urgently needed for treating metastatic breast cancer.In this work, a docetaxel(DTX)-loaded micelle(pDM) as the tumor-microenvironment-responsive delivery platform is developed. The micelle is composed of a pH-sensitive amphiphilic copolymer,poly((1,4-butanediol)-diacrylate-b-N,N-diisopropylethylenediamine)-polyethyleneimine(BD-PEI), and a matrix metalloproteinase(MMP)-responsive polymer, poly((1,4-butanediol)-diacrylate-b-N,N-diisopropy lethylenediamine)-peptide-polyethylene glycol(PEG)(BD-peptide-PEG). The PEG block of BD-peptidePEG will be split by MMPs at the tumor microenvironment, which leads to the change of the surface charge and particle size of the micelle to more positive and smaller one. Owing to this transformation and enhanced permeability and retention(EPR) effect, pDM delivers more DTX into tumor tissues and is internalized more efficiently by tumor cells than the non-MMP-sensitive micelles in the 4 T1 tumorbearing mice model. In addition, DTX is released in acidic endo/lysosomes due to the dissociation of the micelle, triggered by the protonation of the hydrophobic block of BD-PEI. As a result, the DTX-loaded micelle inhibits primary tumor growth and pulmonary metastasis effectively. Thus, this pH/MMP-dual-sensitive drug delivery system, which simultaneously attains three keypoints: prolonged circulation time, directional and efficient uptake into tumor cells, and speedy intracellular drug release, is a promising strategy for metastatic breast cancer therapy.