Biomimetic Nanovesicle with Mitochondria-Synthesized Sonosensitizer and Mitophagy Inhibition for Cancer Sono-Immunotherapy.

Mitochondria are crucial for both sonodynamic therapy and antitumor immunity. However, how to accurately damage mitochondria and meanwhile prevent the mitophagy and immune checkpoint inhibition is still a great challenge. Herein, hexyl 5-aminolevulinate hydrochloride (HAL) and 3-methyladenine (3MA) are loaded into the tumor cell-derived microparticle (X-MP), which can direct the target delivery of the prepared HAL/3MA@X-MP to the tumor cells. HAL induces the confined biosynthesis and accumulation of sonosensitizer PpIX in mitochondria, leading to the localized generation of reactive oxygen species (ROS) upon ultrasound irradiation and, thus, the efficient mitochondrial damage. Meanwhile, 3MA not only inhibits mitophagy but also down-regulates the PD-L1 expression, promoting the immunogenic cell death (ICD) while blocking the immune checkpoint recognition. The smart synergism of precise mitochondrial damage, mitophagy inhibition and antitumor immunity results in potent therapeutic efficacy without obvious side effects.

Bacterial outer membrane vesicle based versatile nanosystem boosts the efferocytosis blockade triggered tumor-specific immunity.

Efferocytosis inhibition is emerging as an attractive strategy for antitumor immune therapy because of the subsequent leak of abundant immunogenic contents. However, the practical efficacy is seriously impeded by the immunosuppressive tumor microenvironments. Here, we construct a versatile nanosystem that can not only inhibit the efferocytosis but also boost the following antitumor immunity. MerTK inhibitor UNC2025 is loaded into the bacterial outer membrane vesicles (OMVs), which are then modified with maleimide (mU@OMVs). The prepared mU@OMVs effectively inhibits the efferocytosis by promoting the uptake while preventing the MerTK phosphorylation of tumor associated macrophages, and then captures the released antigens through forming universal thioether bonds. The obtained in situ vaccine effectively transfers to lymph nodes by virtue of the intrinsic features of OMVs, and then provokes intense immune responses that can efficiently prevent the growth, metastasis and recurrence of tumors in mice, providing a generalizable strategy for cancer immunotherapy.

Phytochemical Engineered Bacterial Outer Membrane Vesicles for Photodynamic Effects Promoted Immunotherapy.

Cancer vaccines are emerging as an attractive modality for tumor immunotherapy. However, their practical application is seriously impeded by the complex fabrication and unsatisfactory outcomes. Herein, we construct bacterial outer membrane vesicles (OMVs)-based in situ cancer vaccine with phytochemical features for photodynamic effects-promoted immunotherapy. By simply fusing thylakoid membranes with OMVs, bacteria-plant hybrid vesicles (BPNs) are prepared. After systemic administration, BPNs can target tumor tissues and stimulate the activation of immune cells, including dendritic cells (DCs). The photodynamic effects derived from thylakoid lead to the disruption of local tumors and then the release of tumor-associated antigens that are effectively presented by DCs, inducing remarkable tumor-specific CD8+T cell responses. Moreover, BPNs can efficiently ameliorate the immunosuppressive tumor microenvironment and further boost immune responses. Therefore, both tumor development and metastasis can be efficiently prevented. This work provides a novel idea for developing a versatile membrane-based hybrid system for highly efficient tumor treatment.

Applications of π-π stacking interactions in the design of drug-delivery systems.

Noncovalent forces are of considerable importance in the formation of self-assembled drug-delivery systems. In addition to non-destructively linking the delivery vehicle and guest drug, they provide multiple advantages, including protecting the structure of the drug, maintaining its functional effects, and facilitating its release. In particular, π-π stacking interactions have potential application in a comprehensive range of biomedical and biotechnological fields. Because they do not alter structural or functional properties of drugs, π-π stacking interactions have been used as a driving force in loading drugs into delivery systems, and in the design of self-assembling systems. Moreover, since the π-π stacking force is affected by environmental conditions such as pH, it has been used to design environment-responsive drug-delivery systems. In this review, we cover features of π-π stacking interactions and their applications to the design of drug-delivery systems. Carbon nanotubes, graphene-based nanomaterials, micelles and hydrogels-all delivery systems capable of π-π stacking interactions-are the focus. We also cover π-π stacking interaction-based loading of chemicals or biological drugs into delivery systems, and controlled release of drugs from delivery systems in certain environments. In addition, we examine the in vivo barriers for π-π stacking interaction-based drug delivery, and discuss challenges for clinical applications and future directions.

A new strategy for hydrophobic drug delivery using a hydrophilic polymer equipped with stacking units.

A highly hydrophilic polymer equipped with guanidinium groups was used to load aromatic ring-containing hydrophobic agent doxorubicin (DOX) via π-π interaction. The results have shown that the delivery system exhibited enhanced cellular uptake and antitumor efficiency compared with free drugs. This study opens new avenues for the application of hydrophilic polymers in drug delivery.