Pancreatic ductal adenocarcinoma (PDAC), one of the most challenging cancers, is uniquely characterized by a biological barrier composed of multiple components in the extracellular matrix, preventing penetration of chemotherapeutic agents and hindering clinical drug treatment. Collagen I arrangement is critical. In this study, gemcitabine is chosen as the chemotherapeutic agent and dasatinib as the collagen-I-disrupting agent. When collagen I arrangement is disrupted, not only the chemotherapeutic drug enters the tumor area better, but the infiltration of CD8+ T cells into the tumor also increases. Therefore, a hypoxia-responsive linker-crosslinked polymer, DGD/L@GBI, is designed, which can be simultaneously loaded with two therapeutic agents, gemcitabine and dasatinib. The polymer is encapsulated by nucleic acid aptamers that target the PDAC stromal microenvironment and shield the surface. The aptamer is removed upon arrival at the PDAC hypoxic microenvironment, exposing the positively charged core to achieve charge reversal. Particle size transformation is achieved using linkers that respond to a hypoxic microenvironment. Increased intratumoral penetration is achieved using the dual transformation capabilities of the formulation. Pairing these two agents can result in a powerful efficacy in chemotherapy sensitization and immune infiltration.

Not only genetic but also epigenetic factors are closely associated with cancer, especially with its malignant evolution. Cancer therapies based on epigenetic modulation have therefore been proposed early on. However, it has produced significant efficacy only in patients with hematological malignancies rather than solid tumors, partly due to the inherent physicochemical properties of the drugs and the impediments to their reaching the tumor cells in vivo. As a result, a growing number of researches have been devoted to extending the use of epigenetic therapies to a wider range of solid tumor treatments by means of drug delivery strategies (DDSs). These studies have provided new insights into the application of epigenetic therapies for cancer and new ideas to address the poor outcome of epigenetic therapy in solid tumors through DDSs. Therefore, this review summarizes the epigenetic factors of cancer, the contribution of the designed DDSs to the anti-tumor treatments (especially solid tumors), the application of different anti-tumor epigenetic therapies based on DDSs, and finally analyses the potential problems in current anti-tumor epigenetic therapies and the great potential of DDSs in their future development.

Targeting the competitive-cooperative relationships among tumor cells and various immune cells can efficiently reverse the immune-dysfunction microenvironment to boost the immunotherapies for the triple-negative breast cancer treatment. Hence, a bacterial outer membrane vesicle-based nanocomplex is designed for specifically targeting malignant cells and immune cells to reconcile the relationships based on metabolic-immune crosstalk. By uniquely utilizing the property of charge-reversal polymers to realize function separation, the nanocomplexes could synergistically regulate tumor cells and immune cells. This approach could reshape the immunosuppressive competition-cooperation pattern into one that is immune-responsive, showcasing significant potential for inducing tumor remission in TNBC models.

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

Pharmaceutical nanotechnology is a modern and unique branch of pharmaceutics based on nanotechnology that shows potential applications in treating diseases. This branch is mainly concerned with nano-scaled formulations with versatile advantages. Pharmaceutical nanotechnology arouse great impact onto the formulation design of both academy and industry. Herein, we reviewed the characteristics of nano-drug delivery systems. Further, we discuss the various types of nanoformulations and their applications. Though still with challenges, pharmaceutical nanotechnology, with no doubt, casts new lights in modulating the drug delivery, optimizing the in vivo distribution and increasing the treating efficacy.

The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is the main block for the penetration of chemotherapy. In the tumor microenvironment, a dense matrix composed of fibrin is formed on the exterior, while the interior is featured by high reduction, hypoxia and low pH. How to match the special microenvironment to on-demand drug release is the key to improve chemotherapeutic efficacy. Herein, a microenvironment-responsive micellar system is developed to deepen tumoral penetration. Briefly, the conjugation of a fibrin-targeting peptide to PEG-poly amino acid has been utilized to achieve accumulation of micelles in the tumor stroma. By modification of micelles with hypoxia-reducible nitroimidazole which becomes protonated under acidic conditions, their surface charge is more positive, facilitating deeper penetration into tumors. Paclitaxel was loaded onto the micelles via a disulfide bond to enable glutathione (GSH)-responsive release. Therefore, the immunosuppressive microenvironment is relived through the alleviation of hypoxia and depletion of GSH. Hopefully, this work could establish paradigms by designing sophisticated drug-delivery systems to tactfully employ and retroact the tamed tumoral microenvironment to improve the therapeutic efficacy based on understanding the multiple hallmarks and learning the mutual regulation.

Breast cancer stem cells (BCSCs) are the culprit of triple-negative breast cancer invasiveness and are heterogeneous. It is recognized that the combination of chemotherapy and differentiation therapy for killing BCSCs and non-BCSCs simultaneously is a reliable strategy. In this study, an oil-in-water nanoemulsion was prepared by high-pressure homogenization with coencapsulation of all-trans retinoic acid (ATRA) and doxorubicin (DOX). The preparation process was simple, and the production was easy to scale up. The particle size of the nanoemulsion was 127.2 ± 2.0 nm. Cellular toxicity assay showed that the composite index of the ATRA and DOX was less than 1 and exhibited a fine combined effect. In vivo antitumor efficacy showed that the compound nanoemulsion could reduce the proportion of BCSCs to 1.18% by inhibiting the expression of Pin1. In addition, the combination of ATRA and DOX could reduce the cardiotoxicity of DOX and had higher safety. Hopefully, this work can provide a new insight into developing pharmaceutically acceptable technology for treating BCSCs.

Reperfusion injury presents a significant obstacle to neuronal survival following successful recanalization in ischemic stroke, which is characterized by intricate pathophysiological processes comprising numerous interconnected pathways. Oxidative stress-induced neuronal ferroptosis and the overactivation of glial cells play important roles in this phenomenon. In this study, we developed a targeted cross-linked micelle loaded with idebenone to rescue the ischemic penumbra by inhibiting neuronal ferroptosis and glial overactivation. In rat models, the CREKA peptide-modified micelles accumulate in the damaged brain via binding to microthrombi in the ipsilateral microvessels. Upon reactive oxygen species (ROS) stimulation, diselenide bonds within the micelles are transformed to hydrophilic seleninic acids, enabling synchronized ROS consumption and responsive drug release. The released idebenone scavenges ROS, prevents oxidative stress-induced neuronal ferroptosis, attenuates glial overactivation, and suppresses pro-inflammatory factors secretion, thereby modulating the inflammatory microenvironment. Finally, this micelle significantly reinforces neuronal survival, reduces infarct volume, and improves behavioral function compared to the control groups. This pleiotropic therapeutic micelle provides a proof-of-concept of remodeling the lesion microenvironment by inhibiting neuronal ferroptosis and glial overactivation to treat cerebral ischemia-reperfusion injury.

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune acti-vation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nano-materials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mecha-nistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8+ T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.

The rapid postoperative recurrence and short survival time of glioblastoma (GBM) patients necessitate immediate and effective postoperative treatment. Herein, an immediate and mild postoperative local treatment strategy is developed that regulates the postoperative microenvironment and delays GBM recurrence. Briefly, an injectable hydrogel system (imGEL) loaded with Zn(II)2 -AMD3100 (AMD-Zn) and CpG oligonucleotide nanoparticles (CpG NPs) is injected into the operation cavity, with long-term function to block the recruitment of microglia/ macrophages and activate cytotoxic T cells. The finding indicated that the imGEL can regulate the immune microenvironment, inhibit GBM recurrence, and gain valuable time for subsequent adjuvant clinical chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is on of the most lethal malignant tumors with relatively poor prognosis, characterized with insufficient drug penetration, low immune response and obvious drug resistances. The therapeutic inefficiency is multifactorially related to its specific tumor microenvironment (TME), which is representatively featured as rich stroma and immunosuppression. In this work, a versatile drug delivery system is developed that can coencapsulate two prodrugs modified from gemcitabine (GEM) and a signal transducer and activator of transcription 3 (STAT3) inhibitor (HJC0152), and the gradient pH variation is further sensed in the TME of PDAC to achieve a higher penetration by reversing its surficial charges. The escorted prodrugs can release GEM intracellularly, and respond to the hypoxic condition to yield the parental STAT3 inhibitor HJC0152, respectively. By inhibiting STAT3, the tumor immunosuppression microenvironment can be re-educated through the reversion of M2-like tumor associated macrophages (M2-TAMs), recruitment of cytotoxic T lymphocytes and downregulation of regulatory T cells (Treg s). Furthermore, cytidine deaminase (CDA) and α-smooth muscle actin (α-SMA) expression can be downregulated, plus the lipid modification of GEM, the drug resistance of GEM can be greatly relieved. Based on the above design, a synergetic therapeutic efficacy in PDAC treatment can be achieved to provide more opportunity for clinical applications.

The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control. Hence, we design and construct an aptamer-decorated hypoxia-responsive nanoparticle s(DGL)n@Apt co-loading gemcitabine monophosphate and STAT3 inhibitor HJC0152. This nanoparticle can reverse its surficial charge in the TME, and reduce the size triggered by hypoxia. The released ultra-small DGL particles loading gemcitabine monophosphate exhibit excellent deep-tumor penetration, chemotherapy drugs endocytosis promotion, and autophagy induction ability. Meanwhile, HJC0152 inhibits overactivated STAT3 in both tumor cells and tumor stroma, softens the stroma barrier, and reeducates the TME into an immune-activated state. This smart codelivery strategy provides an inspiring opportunity in PDAC treatment.

Metabolic interactions between different cell types in the tumor microenvironment (TME) often result in reprogramming of the metabolism to be totally different from their normal physiological processes in order to support tumor growth. Many studies have attempted to inhibit tumor growth and activate tumor immunity by regulating the metabolism of tumors and other cells in TME. However, metabolic inhibitors often suffer from the heterogeneity of tumors, since the favorable metabolic regulation of malignant cells and other cells in TME is often inconsistent with each other. Therefore, we reported the design of a pH-sensitive drug delivery system that targets different cells in TME successively. Outer membrane vesicles (OMVs) derived from Gram-negative bacteria were applied to coload paclitaxel (PTX) and regulated in development and DNA damage response 1 (Redd1)-siRNA and regulate tumor metabolism microenvironment and suppress tumor growth. Our siRNA@M-/PTX-CA-OMVs could first release PTX triggered by the tumor pH (pH 6.8). Then the rest of it would be taken in by M2 macrophages to increase their level of glycolysis. Great potential was observed in TAM repolarization, tumor suppression, tumor immune activation, and TME remolding in the triple-negative breast cancer model. The application of the OMV provided an insight for establishing a codelivery platform for chemical drugs and genetic medicines.

Current therapeutic strategies for Alzheimer's disease (AD) treatments mainly focus on β‐amyloid (Aβ) targeting. However, such therapeutic strategies have limited clinical outcomes due to the chronic and irreversible impairment of the nervous system in the late stage of AD. Recently, inflammatory responses, manifested in oxidative stress and glial cell activation, have been reported as hallmarks in the early stages of AD. Based on the crosstalk between inflammatory response and brain cells, a reactive oxygen species (ROS)‐responsive dendrimer–peptide conjugate (APBP) is devised to target the AD microenvironment and inhibit inflammatory responses at an early stage. With the modification of the targeting peptide, this nanoconjugate can efficiently deliver peptides to the infected regions and restore the antioxidant ability of neurons by activating the nuclear factor (erythroid‐derived 2)‐like 2 signaling pathway. Moreover, this multi‐target strategy exhibits a synergistic function of ROS scavenging, promoting Aβ phagocytosis, and normalizing the glial cell phenotype. As a result, the nanoconjugate can reduce ROS level, decrease Aβ burden, alleviate glial cell activation, and eventually enhance cognitive functions in APPswe/PSEN1dE9 model mice. These results indicate that APBP can be a promising candidate for the multi‐target treatment of AD.

Reperfusion injury is still a major challenge that impedes neuronal survival in ischemic stroke. However, the current clinical treatments are remained on single pathological process, which are due to lack of comprehensive neuroprotective effects. Herein, a macrophage-disguised honeycomb manganese dioxide (MnO2 ) nanosphere loaded with fingolimod (FTY) is developed to salvage the ischemic penumbra. In particular, the biomimetic nanoparticles can accumulate actively in the damaged brain via macrophage-membrane protein-mediated recognition with cell adhesion molecules that are overexpressed on the damaged vascular endothelium. MnO2 nanosphere can consume excess hydrogen peroxide (H2 O2 ) and convert it into desiderated oxygen (O2 ), and can be decomposed in acidic lysosome for cargo release, so as to reduce oxidative stress and promote the transition of M1 microglia to M2 type, eventually reversing the proinflammatory microenvironment and reinforcing the survival of damaged neuron. This biomimetic nanomedicine raises new strategy for multitargeted combined treatment of ischemic stroke.

A versatile tumor-targeting stimuli-responsive theranostic platform for peritoneal metastases of colorectal cancer is proposed in this work for tumor tracking and photothermal-enhanced chemotherapy. A quenched photosensitizer ("off" state) is developed and escorted into a tumor-targeting oxaliplatin-embedded micelle. Once reaching the tumor cell, the micelle is clasped to release free oxaliplatin, as well as the "off" photosensitizer, which is further activated ("turned-on") in the tumor reducing microenvironment to provide optical imaging and photothermal effect. The combined results from hyperthermia-enhanced chemotherapy, deep penetration, perfused O2 , and the leveraged GSH-ROS imbalance in tumor cells are achieved for improved antitumor efficacy and reduced systematic toxicity.