Pancreatic cancer, characterized by dense tissue and a significant infiltration of myeloid-derived suppressor cells (MDSCs), leads to an almost complete absence of T cells infiltration and a poor response to immunotherapy. A strategy involving external defense of MDSCs recruitment and internal attack on tumor cells may enhance the effectiveness of chemo-immunotherapy for pancreatic cancer. Herein, a MDSCs-derived nanovesicle encapsulating the CD11b agonist leukadherin-1 (LA) and the polyamide-oxaliplatin (PAMAM-OXA) nanoparticles (P), named MLR/LA@P, was constructed for pancreatic cancer treatment. The activation of CD11b by LA enhanced the binding of MLR/LA@P to ICAM-1, thereby improving tumor targeting ability and competitively inhibiting MDSCs recruitment for “external defense”. In response to matrix metalloproteinase-2 (MMP2) in the tumor microenvironment, MLR/LA@P degraded and released small-sized P for deep penetration. Subsequently, OXA was released in response to glutathione within tumor cells, triggering immunogenic cell death for “internal attack”. MLR/LA@P not only inhibited the growth of orthotopic pancreatic tumors, but also prevented the formation of pre-metastatic niches (PMNs), which is promising for pancreatic cancer treatment.

Despite the high nucleic acid loading capacity, cationic liposomes (CLs) are facing challenges of insufficient nucleic acid drug release. Ginsenosides, natural product with a steroidal structure similar with cholesterol, not only have the potential to replace cholesterol in modulating the mobility of phospholipid bilayer and the release of nucleic acid drugs, but also exhibit therapeutic activities such as anti-fibrosis capacity. In this study, we screened potential ginsenosides and developed an efficient siRNA delivery ginsenoside liposome by replacing cholesterol with preferred ginsenoside Rb1, aiming for enhanced hepatic fibrosis treatment. To further enhance the targeted internalization to the activated hepatic stellate cells, ginsenoside liposomes were further modified with targeting cell penetrating peptide R8-dGR. Compared with cholesterol liposomes, the optimized Rb1 liposomes effectively enhanced the cellular internalization and gene silencing efficiency using Yes-associated protein (YAP) as a target. Mechanism studies reveal that the replacement of cholesterol with ginsenoside Rb1 allows membrane perturbation upon insertion into the phospholipid bilayer, leading to enhanced cell membrane fusion and lysosomal release of siRNA, which may account for enhanced cell internalization and gene silencing. Combined with the internal antifibrotic activity of ginsenoside and the downregulation of YAP, the functionalized liposome inhibited hepatic stellate cell activation and reversed abnormal extracellular matrix deposition, leading to enhanced anti-hepatic fibrosis activity both in vitro and in vivo. Owing to the transfection-promoting effect and pharmacological activity of ginsenoside Rb1, the ginsenoside liposome represents an efficient siRNA delivery approach for the treatment of hepatic fibrosis.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with high mortality rates and poor prognosis, largely due to the nonspecific drug distribution and suboptimal therapeutic efficacy. To address these challenges, here we proposed a CD44/Transferrin receptor dual targeted self-delivery micelle for the combination delivery of chemotherapeutic doxorubicin (DOX) and artesunate (ART), a natural product known for its ability of killing AML cells by inducing apoptosis. To improve AML targeting, the transferrin receptor targeting peptide T7 was conjugated with CD44 targeting hyaluronic acid (HA), followed by conjugation with hydrophobic ART to afford the amphiphilic polymer for DOX encapsulation (termed THAD). The resulting self-delivery micellar drug delivery system THAD significantly enhanced the cellular internalization of AML cells and facilitated in vivo tumor targeting. Compared with single drug treatment groups, the combination of ART and DOX showed a better tumor killing ability. Furthermore, THAD suppressed the tumor proliferation by 90.74%. Specifically, THAD induced significantly mitochondrial-dependent apoptosis via increasing mitochondrial membranes damage and subsequent G1 phase arrest, as evidenced by the decreased levels of pro-caspase-3 and Bcl-2, along with the increased levels of Bax and cleaved poly(ADP-ribose) polymerase (PARP). Furthermore, THAD inhibited protein kinase B (AKT) phosphorylation, leading to a decrease of c-Myc expression in response to a negative growth regulator. In the human acute myeloid leukemia cells (MOLM13) cell-bearing mouse model, THAD significantly inhibited AML cell infiltration and proliferation in both bone marrow and liver, effectively suppressing AML progression. Collectively, THAD demonstrated enhanced anti-AML effects by promoting apoptosis, offering a promising targeted self-delivery strategy for combination chemotherapy in AML treatment.

Photodynamic therapy (PDT) and ferroptosis therapy have received extensive attention in breast cancer treatment. PDT induced apoptosis of tumor cells by producing a large amount of reactive oxygen species (ROS) under laser irradiation. Differently, ferroptosis therapy exerts its antitumor effect by inducing excessive accumulation of lipid peroxides on tumor cell membranes. Based on that, ROS produced by PDT may promote ferroptosis in tumor cells, and ferroptosis therapy is expected eliminate apoptosis-resistant tumor cells. Therefore, a synergistic ferroptosis-photodynamic therapy will be more effective and more potential in breast cancer treatment. Considering PDT has the characteristic of producing ROS, and neutrophil has a natural tendency to ROS, a neutrophil-mimetic hybrid liposome (CR-NML) was designed for co-delivery of the photosensitizer Ce6 and the ferroptosis inducer RSL3. CR-NML targeted tumor through the ROS tendency of neutrophil and the enhanced permeability and retention (EPR) effect of liposome, then induced both apoptosis and ferroptosis in tumor cells, which increased ROS level and finally realized ROS cascade amplification. The synergistic ferroptosis-photodynamic therapy demonstrated significant therapeutic efficacy in 4T1 tumor bearing mice, which provided a promising strategy for breast cancer treatment.