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The choroid plexus (ChP) serves as the principal origin of cerebrospinal fluid (CSF). CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently. Nevertheless, the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined. In the present study, we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation. Specifically, we identify the chemokine CCL2, released by ChP epithelial cells, recruits CCR2+ monocytes to the ChP thereby inciting hydrocephalus pathogenesis. The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-α/TNFR1/NF-κB signaling cascade, thereby leading to CSF hypersecretion. Strikingly, augmentation of ChP‒CCL2 using an adeno-associated viral approach (AAV) exacerbates macrophage recruitment, activation, and ventriculomegaly in rat PHH models. Systemic application of Bindarit, a specific CCL2 inhibitor, significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate. Furthermore, the administration of CCR2 antagonist (INCB 3284) reduces ChP macrophage accumulation and ventriculomegaly. This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.

Abstract Breast cancer is the most common malignant tumor that threatens women’s life and health, and metastasis often occurs in the advanced stage of breast cancer, leading to pathological bone destruction and seriously reducing patient quality of life. In this study, we coupled chlorin e6 (Ce6) with mono-(6-amino-6-deoxy)-beta-cyclodextrin (β-CD) to form Ce6-CD, and combined ferrocene with the FFVLG3C peptide and PEG chains to form the triblock molecule Fc-pep-PEG. In addition, the IDO-1 inhibitor NLG919 was loaded with Ce6-CD and Fc-pep-PEG to construct the supramolecular nanoparticle NLG919@Ce6-CD/Fc-pep-PEG (NLG919@CF). After laser irradiation, Ce6 produced robust reactive oxidative species to induce tumor cell apoptosis. Simultaneously, ferrocene became charged, and Fc-pep-PEG dissociated from the spherical nanoparticles, enabling their transformation into nanofibers, which increased both the retention effect and the induction of ferroptosis. The released NLG919 reduced the number of regulatory T cells (Tregs) and restored the function of cytotoxic T lymphocytes (CTLs) by inhibiting the activity of IDO-1. Moreover, combined administration with an anti-PD-1 antibody further relieved immune suppression in the tumor microenvironment. This article presents a new strategy for the clinical treatment of breast cancer with bone metastasis and osteolysis. Graphical Abstract

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

Abstract Dysfunction of the hypothalamus is associated with endocrine imbalances, growth abnormalities, and reproductive disorders. However, there is a lack of targeted treatment strategies focused on the hypothalamus. In this study, we constructed a multifunctional nanocarrier system (S@ANP) to directly target the hypothalamic neurokinin receptor 3 (NK3R) via an intranasal delivery strategy. This system could overcome the primary obstacles in drug delivery for hypothalamus‐related diseases. Under the guidance of a modified (Trp7, β‐Ala8)‐neurokinin A (4‐10) peptide with cysteine, nanoparticles encapsulated with SB222200, an NK3R inhibitor, were found to readily penetrate hypothalamic cells with substantial loading capacity, encapsulation efficiency, and sustained release in vitro. Moreover, intranasal delivery represents an optimal delivery strategy that allows for a significant reduction in oral dosage and enables nanoparticles to bypass the blood‒brain barrier and target relevant parts of the brain. The mucolytic agent N‐acetyl‐L‐cysteine (NAC) was loaded into the nanoparticles (S@ANP + NAC) to increase mucosal solubility and intranasal delivery efficiency. In vivo evaluations showed that S@ANP + NAC could effectively target the hypothalamus and modulate NK3R‐regulated hypothalamic functions in mice. Due to its high hypothalamic targeting efficiency and low toxicity, this intranasal nanoparticle drug delivery system may serve as a potential strategy for precision therapy of hypothalamic disorders.

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

A special microenvironment called the “pre-metastatic niche” is thought to help primary tumor cells migrate to new tissues and invade them, in part because the normal barrier function of the vascular endothelium is compromised. While the primary tumor itself can promote the creation of such niches by secreting pro-metastatic factors, the underlying molecular mechanisms are still poorly understood. Here, we show that the injection of primary tumor-secreted pro-metastatic factors from B16F10 melanoma or 4T1 breast cancer cells into healthy mice can induce the destruction of the vascular endothelial glycocalyx, which is a polysaccharide coating on the vascular endothelial lumen that normally inhibits tumor cell passage into and out of the circulation. However, when human umbilical vein endothelial cultures were treated in vitro with these secreted pro-metastatic factors, no significant destruction of the glycocalyx was observed, implying that this destruction requires a complex in vivo microenvironment. The tissue section analysis revealed that secreted pro-metastatic factors could clearly upregulate macrophage-related molecules such as CD11b and tumor necrosis factor-α (TNF-α) in the heart, liver, spleen, lung, and kidney, which is associated with the upregulation and activation of heparanase. In addition, macrophage depletion significantly attenuated the degradation of the vascular endothelial glycocalyx induced by secreted pro-metastatic factors. This indicates that the secreted pro-metastatic factors that destroy the vascular endothelial glycocalyx rely primarily on macrophages. Our findings suggest that the formation of pre-metastatic niches involves degradation of the vascular endothelial glycocalyx, which may hence be a useful target for developing therapies to inhibit cancer metastasis.

As known, the benefits of photothermal therapy (PTT) are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins (HSPs). Then HSPs further trigger the formation of stress granules (SGs) that regulate protein expression and cell viability under various stress conditions. Inhibition of SG formation can sensitize tumor cells to PTT. Herein, we developed PEGylated pH (low) insertion peptide (PEG-pHLIP)-modified hollow copper sulfide nanoparticles (HCuS NPs) encapsulating the SG inhibitor ISRIB, with the phase-change material lauric acid (LA) as a gate-keeper, to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system (IL@H-PP). The nanomedicine could specifically target slightly acidic tumor sites. Upon irradiation, IL@H-PP realized PTT, and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT, thereby increasing the antitumor effect and inducing potent immunogenic cell death (ICD). Moreover, IL@H-PP could promote the production of reactive oxygen species (ROS) by tumor-associated macrophages (TAMs), repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment. In vitro/vivo results revealed the potential of PTT combined with SG inhibitors, which provides a new paradigm for antitumor and anti-metastases.

Abstract Breast cancer bone metastasis has become a common cancer type that still lacks an effective treatment method. Although epigenetic drugs have demonstrated promise in cancer therapy, their nontargeted accumulation and drug resistance remain nonnegligible limiting factors. Herein, we first found that icaritin had a strong synergistic effect with an epigenetic drug (JQ1) in the suppression of breast cancer, which could help to relieve drug resistance to JQ1. To improve tumor-targeted efficacy, we developed a hypoxia-cleavable, RGD peptide-modified poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle (termed ARNP) for the targeted delivery of JQ1 and icaritin. The decoration of long cleavable PEG chains can shield RGD peptides during blood circulation and reduce cellular uptake at nonspecific sites. ARNP actively targets breast cancer cells via an RGD-αvβ3 integrin interaction after PEG chain cleavage by responding to hypoxic tumor microenvironment. In vitro and in vivo assays revealed that ARNP exhibited good biodistribution and effectively suppressed primary tumor and bone metastasis. Meanwhile, ARNP could alleviate bone erosion to a certain extent. Furthermore, ARNP significantly inhibited pulmonary metastasis secondary to bone metastasis. The present study suggests that ARNP has great promise in the treatment of breast cancer and bone metastasis due to its simple and practical potential.

Abstract Cancer immunotherapy using anti‐programmed death‐ligand 1 (PD‐L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD‐L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD‐L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD‐L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD‐L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD‐L1 can fundamentally transform the current status of PD‐L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD‐L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD‐L1 (including mPD‐L1, cPD‐L1, nPD‐L1, and exoPD‐L1). Then an in‐depth analysis of the regulatory mechanisms and potential therapeutic targets of PD‐L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD‐L1 therapeutics strategies.

The therapeutic modes of cancers have been profoundly renovated by immunotherapies, which have shown extraordinary treating efficacy in certain tumor entities. However, the majority of cancer patients have not profited from it because of the negative effects of tumor microenvironment (TME) on human innate and/or adaptive immunity, including hypoxia, acidification, irregular vasculature, and a plethora of immunosuppressive cells and small molecules, which contribute to tumor progression, migration, resistance to drug, and so forth. Accordingly, it is feasible to enhance the efficacy of immunotherapies and increase the patients’ survival through the restructure of TME. Herein, the mechanisms and reverberations of aforementioned immunosuppressive elements are concentrated on, and latest therapeutic achievements and combined technologies that have been demonstrated effective in boosting immunotherapies by TME modulation are enumerated.

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). This targeted liposome is prepared through a mature preparation process, and indoleamine-2,3-dioxygenase (IDO) inhibitor NLG919 was encapsulated into it. Moreover, mediated by the enhanced permeability and retention effect (EPR effect) and AUNP-12, NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues. At the same time, the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12, thus realizing the precise block of PD-1 signal pathway, and restoring the activity of T cells. The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

Introduction: Blood-brain barrier with strictly controlled activity participates in a coordinated transfer of bioactive molecules from the blood to the brain. Among different delivery approaches, gene delivery is touted as a promising strategy for the treatment of several nervous system disorders. The transfer of exogenous genetic elements is limited by the paucity of suitable carriers. As a correlate, designing high-efficiency biocarriers for gene delivery is challenging. This study aimed to deliver pEGFP-N1 plasmid into the brain parenchyma using CDX-modified chitosan (CS) nanoparticles (NPs). Methods: Herein, we attached CDX, a 16 amino acids peptide, to the CS polymer using bifunctional polyethylene glycol (PEG) formulated with sodium tripolyphosphate (TPP), by ionic gelation method. Developed NPs and their nanocomplexes with pEGFP-N1 (CS-PEG-CDX/pEGFP) were characterized using DLS, NMR, FTIR, and TEM analyses. For in vitro assays, a rat C6 glioma cell line was used for cell internalization efficiency. The biodistribution and brain localization of nanocomplexes were studied in a mouse model after intraperitoneal injection using in vivo imaging and fluorescent microscopy. Results: Our results showed that CS-PEG-CDX/pEGFP NPs were uptaken by glioma cells in a dose-dependent manner. In vivo imaging revealed successful entry into the brain parenchyma indicated with the expression of green fluorescent protein (GFP) as a reporter protein. However, the biodistribution of developed NPs was also evident in other organs especially the spleen, liver, heart, and kidneys. Conclusion: Based on our results, CS-PEG-CDX NPs can provide a safe and effective nanocarrier for brain gene delivery into the central nervous system (CNS).

The tumor microenvironment (TME) plays an important role in the process of tumorigenesis, regulating the growth, metabolism, proliferation, and invasion of cancer cells, as well as contributing to tumor resistance to the conventional chemoradiotherapies. Several types of cells with relatively stable phenotypes have been identified within the TME, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), neutrophils, and natural killer (NK) cells, which have been shown to modulate cancer cell proliferation, metastasis, and interaction with the immune system, thus promoting tumor heterogeneity. Growing evidence suggests that tumor-cell-derived extracellular vesicles (EVs), via the transfer of various molecules (e.g., RNA, proteins, peptides, and lipids), play a pivotal role in the transformation of normal cells in the TME into their tumor-associated protumorigenic counterparts. This review article focuses on the functions of EVs in the modulation of the TME with a view to how exosomes contribute to the transformation of normal cells, as well as their importance for cancer diagnosis and therapy.

Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies, on account of its good safety and long-term memory ability. Discouragingly, low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside. However, it has become evident that, although the immunosuppressive tumor microenvironment (TME) plays a pivotal role in facilitating tumor progression and metastasis, it also provides various potential targets for remodeling the immunosuppressive TME, which can consequently bolster the effectiveness of antitumor response and tumor suppression. Additionally, the particular characteristics of TME, in turn, can be exploited as avenues for designing diverse precise targeting nanomedicines. In general, it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME, thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy. Herein, we will illustrate several formation mechanisms of immunosuppressive TME. More importantly, a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients' immune systems, will be reviewed. Ultimately, we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy. Hopefully, the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.

Abstract In the biomedical and pharmaceutical fields, cyclodextrin (CD) is undoubtedly one of the most frequently used macrocyclic compounds as the host molecule because it has good biocompatibility and can increase the solubility, bioavailability, and stability of hydrophobic drug guests. In this review, we generalized the unique properties of CDs, CD‐related supramolecular nanocarriers, supramolecular controlled release systems, and targeting systems based on CDs, and introduced the paradigms of these nanomedicines. In addition, we also discussed the prospects and challenges of CD‐based supramolecular nanomedicines to facilitate the development and clinical translation of these nanomedicines.

Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention, which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6 (Ce6), hydrophilic chemotherapeutic drug berberrubine (BBR) and matrix metalloproteinase-2 (MMP-2) response peptide (PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6 (BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine (PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively, we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.

Acute liver injury (ALI) has an elevated fatality rate due to untimely and ineffective treatment. Although, schisandrin B (SchB) has been extensively used to treat diverse liver diseases, its therapeutic efficacy on ALI was limited due to its high hydrophobicity. Palmitic acid-modified serum albumin (PSA) is not only an effective carrier for hydrophobic drugs, but also has a superb targeting effect via scavenger receptor-A (SR-A) on the M1 macrophages, which are potential therapeutic targets for ALI. Compared with the common macrophage-targeted delivery systems, PSA enables site-specific drug delivery to reduce off-target toxicity. Herein, we prepared SchB-PSA nanoparticles and further assessed their therapeutic effect on ALI. In vitro, compared with human serum albumin encapsulated SchB nanoparticles (SchB-HSA NPs), the SchB-PSA NPs exhibited more potent cytotoxicity on lipopolysaccharide (LPS) stimulated Raw264.7 (LAR) cells, and LAR cells took up PSA NPs 8.79 times more than HSA NPs. As expected, the PSA NPs also accumulated more in the liver. Moreover, SchB-PSA NPs dramatically reduced the activation of NF-κB signaling, and significantly relieved inflammatory response and hepatic necrosis. Notably, the high dose of SchB-PSA NPs improved the survival rate in 72 h of ALI mice to 75%. Hence, SchB-PSA NPs are promising to treat ALI.

Abstract Reactive oxygen species (ROS) are closely associated with the progression of diabetic cardiomyopathy (DCM) and can be regarded as one of its early biomarkers. Magnetic resonance imaging (MRI) is emerging as a powerful tool for the detection of cardiac abnormalities, but the sensitive and direct ROS‐response MRI probe remains to be developed. This restricts the early diagnosis of DCM and prevents timely clinical interventions, resulting in serious and irreversible pathophysiological abnormalities. Herein, a novel ROS‐response contrast‐enhanced MRI nanoprobe (RCMN) is developed by multi‐functionalizing fluorinated carbon nanosheets (FCNs) with multi‐hydroxyl and 2,2,6,6‐tetramethylpiperidin‐1‐oxyl groups. RCMNs capture ROS and then gather in the heart provisionally, which triggers MRI signal changes to realize the in vivo detection of ROS. In contrast to the clinical MRI agents, the cardiac abnormalities of disease mice is detected 8 weeks in advance with the assistance of RCMNs, which greatly advances the diagnostic window of DCM. To the best of the knowledge, this is the first ROS‐response metal‐free T2‐weighted MRI probe for the early diagnosis of DCM mice model. Furthermore, RCMNs can timely scavenge excessively produced ROS to alleviate oxidative stress.

Many studies have shown the influence of protein corona (PC) on the active targeting capability of ligand-modified nanoparticles; however, the influence of clinical status on PC composition and targeting capacity is rarely discussed. In this study, when transferrin-modified PEGylated polystyrene nanoparticles (Tf-PNs) is intravenously injected into mice with non-small cell lung cancer (NSCLC) comorbid with type 2 diabetes mellitus (T2DM), more Tf-PNs accumulated in the tumor tissue than in those of NSCLC model mice. This indicated that PC derived from different states of disease changed the active targeting ability of Tf-PNs. To explain the occurrence of this phenomenon, our analysis of PC from different disease states revealed that Tf (transferrin) modification had no significant effect on the formation of PC, and that the PC from the NSCLC comorbid with T2DM model contained more proteins like fibrin and clusterin. This work demonstrates the impacts of comorbidity, such as with T2DM, on the active targeting capability of ligand-modified nanoparticles, and the results promote the application of nanoparticles for precision medicine.

The treatment of Alzheimer's disease (AD) is one of the most difficult challenges in neurodegenerative diseases due to the insufficient blood‒brain barrier (BBB) permeability and unsatisfactory intra-brain distribution of drugs. Therefore, we established an ibuprofen and FK506 encapsulated drug co-delivery system (Ibu&FK@RNPs), which can target the receptor of advanced glycation endproducts (RAGE) and response to the high level of reactive oxygen species (ROS) in AD. RAGE is highly and specifically expressed on the lesion neurovascular unit of AD, this property helps to improve targeting specificity of the system and reduce unselective distribution in normal brain. Meanwhile, these two drugs can be specifically released in astrocytes of AD lesion in response to high levels of ROS. As a result, the cognition of AD mice was significantly improved and the quantity of Aβ plaques was decreased. Neurotoxicity was also alleviated with structural regeneration and functional recovery of neurons. Besides, the neuroinflammation dominated by NF-κB pathway was significantly inhibited with decreased NF-κB and IL-1β in the brain. Overall, Ibu&FK@RNPs can efficiently and successively target diseased BBB and astrocytes in AD lesion. Thus it significantly enhances intracephalic accumulation of drugs and efficiently treats AD by anti-neuroinflammation and neuroprotection.

The combination of Ce6, an acknowledged photosensitizer, and TPL, a natural anticancer agent, has been demonstrated as a useful strategy to reinforce the tumor growth suppression, as well as decrease the systemic side effects compared with their monotherapy. However, in view of the optimal chemo-photodynamic combination efficiency, there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL, and stimuli-responsively burst release drugs in tumor site. Herein, we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem, mediated by the host–guest complexing between β-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG, showing the shell–core structural micelles with the tight β-CD layer coating. Both Ce6 and TPL were facilely co-loaded into the spherical supramolecular NPs (TPL+Ce6/NPs) by one-step nanoprecipitation method, with an ideal particle size (156.0 nm), acid pH-responsive drug release profile, and enhanced cellular internalization capacity. In view of the combination benefit of photodynamic therapy and chemotherapy, as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs, TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation, boost ROS level, lower MMP, and promote cellular apoptosis in vitro. Particularly, fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area, with higher intensity than that of free Ce6. As expected, upon 650-nm laser irradiation, TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearing mice and B16 tumor-bearing mice. More importantly, lower systemic toxicity was found in the tumor-bearing mice treated with TPL+Ce6/NPs. Overall, the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

Abstract Pulmonary drug delivery is a highly attractive topic for the treatment of infectious lung diseases. Drug delivery via the pulmonary route offers unique advantages of no first-pass effect and high bioavailability, which provides an important means to deliver therapeutics directly to lung lesions. Starting from the structural characteristics of the lungs and the biological barriers for achieving efficient delivery, we aim to review literatures in the past decade regarding the pulmonary delivery strategies used to treat infectious lung diseases. Hopefully, this review article offers new insights into the future development of therapeutic strategies against pulmonary infectious diseases from a delivery point of view. Graphical Abstract

Considering that photodynamic therapy (PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac (Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species (ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A (LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1α (HIF-1α) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.

The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability, simple preparation method, and offering “all-in-one” functional platform features. However, the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey, which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment. In this review, we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy, including optimizing the intrinsic physicochemical properties and external modification. Finally, the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented. We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.

Inflammatory responses, manifested in excessive oxidative stress and microglia overactivation, together with metal ion-triggered amyloid-beta (Aβ) deposition, are critical hallmarks of Alzheimer’s disease (AD). The intricate pathogenesis causes severe impairment of neurons, which, in turn, exacerbates Aβ aggregation and facilitates AD progression. Herein, multifunctional melanin-like metal ion chelators and neuroinflammation regulators (named PDA@K) were constructed for targeted treatment of AD. In this platform, intrinsically bioactive material polydopamine nanoparticles (PDA) with potent metal ion chelating and ROS scavenging effects were decorated with the KLVFF peptide, endowing the system with the capacity of enhanced pathological blood–brain barrier (BBB) crossing and lesion site accumulation via Aβ hitchhiking. In vitro and in vivo experiment revealed that PDA@K had high affinity toward Aβ and were able to hitch a ride on Aβ to achieve increased pathological BBB crossing. The engineered PDA@K effectively mitigated Aβ aggregate and alleviated neuroinflammation. The modulated inflammatory microenvironment by PDA@K promoted microglial polarization toward the M2-like phenotype, which restored their critical functions for neuron care and plaque removal. After 3-week treatment of PDA@K, spatial learning and memory deficit as well as neurologic changes of FAD4T transgenic mice were largely rescued. Transcriptomics analysis further revealed the therapeutic mechanism of PDA@K. Our study provided an appealing paradigm for directly utilizing intrinsic properties of nanomaterials as therapeutics for AD instead of just using them as nanocarriers, which largely widen the application of nanomaterials in AD therapy.

Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβ deposition or TAU protein need to be resolved urgently. Herein, a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD]. DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions, and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma. Then exposed KLVFF can capture and carry Aβ to microglia, attenuating Aβ-induced neurotoxicity. Strikingly, rapamycin, an autophagy promoter, is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβ degradation and normalize inflammatory condition. This design altogether accelerates Aβ degradation and alleviates oxidative stress and excessive inflammatory response. Collectively, our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment, to achieve efficient AD therapy.

Solid tumors always exhibit local hypoxia, resulting in the high metastasis and inertness to chemotherapy. Reconstruction of hypoxic tumor microenvironment (TME) is considered a potential therapy compared to directly killing tumor cells. However, the insufficient oxygen delivery to deep tumor and the confronting “Warburg effect” compromise the efficacy of hypoxia alleviation. Herein, we construct a cascade enzyme-powered nanomotor (NM-si), which can simultaneously provide sufficient oxygen in deep tumor and inhibit the aerobic glycolysis to potentiate anti-metastasis in chemotherapy. Catalase (Cat) and glucose oxidase (GOx) are co-adsorbed on our previously reported CAuNCs@HA to form self-propelled nanomotor (NM), with hexokinase-2 (HK-2) siRNA further condensed (NM-si). The persistent production of oxygen bubbles from the cascade enzymatic reaction propels NM-si to move forward autonomously and in a controllable direction along H2O2 gradient towards deep tumor, with hypoxia successfully alleviated in the meantime. The autonomous movement also facilitates NM-si with lysosome escaping for efficient HK-2 knockdown to inhibit glycolysis. In vivo results demonstrated a promising anti-metastasis effect of commercially available albumin-bound paclitaxel (PTX@HSA) after pre-treated with NM-si for TME reconstruction. This cascade enzyme-powered nanomotor provides a potential prospect in reversing the hypoxic TME and metabolic pathway for reinforced anti-metastasis of chemotherapy.

Nano- and microemulsions are colloidal systems that are widely used in various fields of biomedicine, including wound and burn healing, cosmetology, the development of antibacterial and antiviral drugs, oncology, etc. The stability of these systems is governed by the balance of molecular interactions between nanodomains. Microemulsions as a colloidal form play a special important role in stability. The microemulsion is the thermodynamically stable phase from oil, water, surfactant and co-surfactant which forms the surface of drops with very small surface energy. The last phenomena determines the shortage time of all fluid dispersions including nanoemulsions and emulgels. This review examines the theory and main methods of obtaining nano- and microemulsions, particularly focusing on the structure of microemulsions and methods for emulsion analysis. Additionally, we have analyzed the main preclinical and clinical studies in the field of wound healing and the use of emulsions in cancer therapy, emphasizing the prospects for further developments in this area.

Type I interferons, particularly IFNα-2b, play essential roles in eliciting adaptive and innate immune responses, being implicated in the pathogenesis of various diseases, including cancer, and autoimmune and infectious diseases. Therefore, the development of a highly sensitive platform for analysis of either IFNα-2b or anti-IFNα-2b antibodies is of high importance to improve the diagnosis of various pathologies associated with the IFNα-2b disbalance. For evaluation of the anti-IFNα-2b antibody level, we have synthesized superparamagnetic iron oxide nanoparticles (SPIONs) coupled with the recombinant human IFNα-2b protein (SPIONs@IFNα-2b). Employing a magnetic relaxation switching assay (MRSw)-based nanosensor, we detected picomolar concentrations (0.36 pg/mL) of anti-INFα-2b antibodies. The high sensitivity of the real-time antibodies’ detection was ensured by the specificity of immune responses and the maintenance of resonance conditions for water spins by choosing a high-frequency filling of short radio-frequency pulses of the generator. The formation of a complex of the SPIONs@IFNα-2b nanoparticles with the anti-INFα-2b antibodies led to a cascade process of the formation of nanoparticle clusters, which was further enhanced by exposure to a strong (7.1 T) homogenous magnetic field. Obtained magnetic conjugates exhibited high negative MR contrast-enhancing properties (as shown by NMR studies) that were also preserved when particles were administered in vivo. Thus, we observed a 1.2-fold decrease of the T2 relaxation time in the liver following administration of magnetic conjugates as compared to the control. In conclusion, the developed MRSw assay based on SPIONs@IFNα-2b nanoparticles represents an alternative immunological probe for the estimation of anti-IFNα-2b antibodies that could be further employed in clinical studies.

Accurate tumor targeting, deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine. To achieve these requirements, a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer (d-SN38)-loaded nanoparticles (d-SN38@NPs/iRGD). Upon intravenous injection, d-SN38@NPs with high drug loading efficiency (33.92 ± 1.33%) could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD. The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy. The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm, which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor. In vitro, co-administering iRGD with d-SN38@NPs+laser showed higher cellular uptake, apoptosis ratio and multicellular spheroid penetration. In vivo, d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor, leading to 60.89% of tumor suppression in 4T1 tumor-bearing mouse model with a favorable toxicity profile. Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting, penetrating and retention, and empowers anticancer efficacy.

Abstract The past decade has witnessed the explosive development of cancer immunotherapies. Nevertheless, low immunogenicity, limited specificity, poor delivery efficiency, and off‐target side effects remain to be the major limitations for broad implementation of cancer immunotherapies to patient bedside. Encouragingly, advanced biomaterials offering cell‐specific modulation of immunological cues bring new solutions for improving the therapeutic efficacy while relieving side effect risks. In this review, focus is given on how functional biomaterials can enable cell‐specific modulation of cancer immunotherapy within the cancer‐immune cycle, with particular emphasis on antigen‐presenting cells (APCs), T cells, and tumor microenvironment (TME)‐resident cells. By reviewing the current progress in biomaterial‐based cancer immunotherapy, here the aim is to provide a better understanding of biomaterials’ role in targeting modulation of antitumor immunity step‐by‐step and guidelines for rationally developing targeting biomaterials for more personalized cancer immunotherapy. Moreover, the current challenge and future perspective regarding the potential application and clinical translation will also be discussed.

Abstract The treatment of autism spectrum disorder (ASD) is one of the most difficult challenges in neurodevelopmental diseases, because of the unclear pathogenesis research and low brain‐lesion targeting efficiency. Besides, maternal immune activation has been reported as the most mature and widely used model of ASD and aspirin‐triggered lipoxin A4 is a potent anti‐inflammatory mediator being involved in the resolution of neuroinflammation in ASD. Therefore, an aspirin encapsulated cascade drug delivery system (Asp@TMNPs) is established, which can successively target the blood–brain barrier (BBB) and microglial cells and response to the acid microenvironment in lysosome. As a result, the mitochondrial oxidative stress, DNA damage, and inflammation of microglial cells are prominently alleviated. After the treatment of Asp@TMNPs, the social interaction, stereotype behavior, and anxious condition of ASD mice are notably improved and the activation of microglial cells is inhibited. Overall, this system successively penetrates the BBB and targets microglial cells, therefore, it significantly enhances the intracephalic drug accumulation and improves anti‐neuroinflammatory efficacy of aspirin, providing a promising strategy for ASD treatment.

In order to better evaluate the transport effect of nanoparticles through the nasal mucosa, an in vitro nasal cavity-mimic model was designed based on M cells. The differentiation of M cells was induced by co-culture of Calu-3 and Raji cells in invert model. The ZO-1 protein staining and the transport of fluorescein sodium and dexamethasone showed that the inverted co-culture model formed a dense monolayer and possessed the transport ability. The differentiation of M cells was observed by up-regulated expression of Sialyl Lewis A antigen (SLAA) and integrin β1, and down-regulated activity of alkaline phosphatase. After targeting M cells with iRGD peptide (cRGDKGPDC), the transport of nanoparticles increased. In vivo, the co-administration of iRGD could result in the increase of nanoparticles transported to the brain through the nasal cavity after intranasal administration. In the evaluation of immune effect in vivo, the nasal administration of OVA-PLGA/iRGD led to more release of IgG, IFN-γ, IL-2 and secretory IgA (sIgA) compared with OVA@PLGA group. Collectively, the study constructed in vitro M cell model, and proved the enhanced effect of targeting towards M cell with iRGD on improving nasal immunity.

Abstract The past decades have witnessed great progress in cancer immunotherapy, which has profoundly revolutionized oncology, whereas low patient response rates and potential immune‐related adverse events remain major clinical challenges. With the advantages of controlled delivery and modular flexibility, cancer nanomedicine has offered opportunities to strengthen antitumor immune responses and to sensitize tumor to immunotherapy. Furthermore, tumor‐microenvironment (TME)‐responsive nanomedicine has been demonstrated to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner, increasing patient response rates to immunotherapy and reducing the immune‐related side effects simultaneously. Here, the recent progress of TME‐responsive nanomedicine for cancer immunotherapy is summarized, which responds to the signals in the TME, such as weak acidity, reductive environment, high‐level reactive oxygen species, hypoxia, overexpressed enzymes, and high‐level adenosine triphosphate. Moreover, the potential to combine nanomedicine‐based therapy and immunotherapeutic strategies to overcome each step of the cancer‐immunity cycle and to enhance antitumor effects is discussed. Finally, existing challenges and further perspectives in this rising field with the hope for improved development of clinical applications are discussed.

Abstract The blood–brain barrier (BBB) is a highly regulated and efficient barrier that controls the mass transfer between blood and brain, severely limits brain penetration of systemically administered therapeutics. During the onset and progression of brain tumors, BBB alters, and the blood–brain tumor barrier (BBTB) forms. Though BBTB differs from BBB in certain aspects, such as neuronal connections and aberrant pericyte distribution, it retains critical aspects of BBB. Hence, one major challenge in the development of therapeutics for brain tumor is to achieve sufficient BBTB penetration thus improving the efficiency of drug delivery to the tumor site. In this review, we summarize the strategies that can overcome BBTB and improve BBTB penetration efficiency from the perspectives of regulating BBTB structure and transport processes.

Although drug delivery systems (DDS) are efficient in brain delivery, they face failure in clinical settings due to their potential toxicity to the central nervous system. Little is known about where the DDS will go after brain delivery, and no specific elimination route that shares a passage with DDS has been verified. Hence, identifying harmless DDS for brain delivery and determining their fate there would strongly contribute to their clinical translation. In this study, we investigated nonreactive gold nanoclusters, which can deliver into the brain, to determine the elimination route of DDS. Subsequently, nanoclusters in the brain were systemically tracked and were found to be critically drained by the glymphatic system from the blood vessel basement membrane to periphery circulations (77.8 ± 23.2% and 43.7 ± 23.4% contribution). Furthermore, the nanoclusters could be actively transported across the blood-brain barrier (BBB) by exosomes (30.5 ± 27.3% and 29.2 ± 7.1% contribution). In addition, microglia promoted glymphatic drainage and passage across the BBB. The simultaneous work of the glymphatic system, BBB, and microglia revealed the fate of gold nanoclusters for brain delivery and provided a basis for further brain-delivery DDS.

Although chemotherapy is an important treatment for advanced prostate cancer, its efficacy is relatively limited. Ultrasound-induced cavitation plays an important role in drug delivery and gene transfection. However, whether cavitation can improve the efficacy of chemotherapy for prostate cancer remains unclear. In this study, we treated RM-1 mouse prostate carcinoma cells with a combination of ultrasound-mediated microbubble cavitation and paclitaxel. Our results showed that combination therapy led to a more pronounced inhibition of cell viability and increased cell apoptosis. The enhanced efficacy of chemotherapy was attributed to the increased cell permeability induced by cavitation. Importantly, compared with chemotherapy alone (nab-paclitaxel), chemotherapy combined with ultrasound-mediated microbubble cavitation significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice in an orthotopic mouse model of RM-1 prostate carcinoma, indicating the synergistic effects of combined therapy on tumor reduction. Furthermore, we analyzed tumor-infiltrating lymphocytes and found that during chemotherapy, the proportions of CTLA4+ cells and PD-1+/CTLA4+ cells in CD8+ T cells slightly increased after cavitation treatment.

Magnetic nanocarriers have attracted attention in translational oncology due to their ability to be employed both for tumor diagnostics and therapy. This review summarizes data on applications of synthetic and biogenic magnetic nanoparticles (MNPs) in oncological theranostics and related areas. The basics of both types of MNPs including synthesis approaches, structure, and physicochemical properties are discussed. The properties of synthetic MNPs and biogenic MNPs are compared with regard to their antitumor therapeutic efficiency, diagnostic potential, biocompatibility, and cellular toxicity. The comparative analysis demonstrates that both synthetic and biogenic MNPs could be efficiently used for cancer theranostics, including biosensorics and drug delivery. At the same time, reduced toxicity of biogenic particles was noted, which makes them advantageous for in vivo applications, such as drug delivery, or MRI imaging of tumors. Adaptability to surface modification based on natural biochemical processes is also noted, as well as good compatibility with tumor cells and proliferation in them. Advances in the bionanotechnology field should lead to the implementation of MNPs in clinical trials.

Hyaluronic acid (HA) is a natural polysaccharide that has gained much attention due to its biocompatibility, enzyme degradation capacity and active tumor targeting capacity. Its receptor, CD44, is overexpressed in many kinds of cancers and is associated with tumor progress, infiltration and metastasis. Therefore, many researchers have developed various HA-based drug delivery systems for CD44-mediated tumor targeting. In this review, we systemically overview the basic theory of HA, its receptor and hyaluronidase, then we categorize the studies in HA-based drug delivery systems according to the functions of HA, including tumor-targeting materials, enzyme-sensitive biodegradable modality, pH-sensitive component, reduction-sensitive component, and the gel backbone. Finally, the perspective is discussed. Key words: Hyaluronic acid, Tumor-active targeting, CD44, Tumor microenvironment, Reduction-sensitive, Enzyme-sensitive, Nanoparticles

Drug delivery systems (DDS) are defined as methods by which drugs are delivered to desired tissues, organs, cells and subcellular organs for drug release and absorption through a variety of drug carriers. Its usual purpose to improve the pharmacological activities of therapeutic drugs and to overcome problems such as limited solubility, drug aggregation, low bioavailability, poor biodistribution, lack of selectivity, or to reduce the side effects of therapeutic drugs. During 2015–2018, significant progress in the research on drug delivery systems has been achieved along with advances in related fields, such as pharmaceutical sciences, material sciences and biomedical sciences. This review provides a concise overview of current progress in this research area through its focus on the delivery strategies, construction techniques and specific examples. It is a valuable reference for pharmaceutical scientists who want to learn more about the design of drug delivery systems. KEY WORDS: Pharmaceutics, Drug delivery system, Basic research, Application, Delivery strategy

Nitric oxide (NO) shows great role in tumor biology. Recent years, more and more researches utilized NO donor in tumor targeting drug delivery and treatment. In this review, we summarized the NO donors by their endogenous and exogenous stimuli. Then the application of NO donors, which was the main aim of the review, was discussed in detailed according to their functions, including inducing tumor cell apoptosis, reversing tumor multidrug resistance, inhibiting tumor metastasis and improving drug delivery. Keywords: Nitric oxide donor, Multidrug resistance, Tumor metastasis, Enhanced permeability and retention effect

Although progress has been indeed made by nanomedicines, their efficacies for cancer treatment remain low, consequently leading to failures in translation to clinic. To improve the drug delivery efficiency, nanoparticles need to change size so as to fully utilize the enhanced permeability and retention (EPR) effect of solid tumor, which is the golden principle of nanoparticles used for cancer treatment. Herein, we employed cationic small-sized red emission bovine serum albumin (BSA) protected gold nanocluster (AuNC@CBSA, 21.06 nm) to both load indocyanine green (ICG) and act as imaging probe to realize theranostic. Then AuNC@CBSA-ICG was fabricated with negatively charged hyaluronic acid (HA) to form AuNC@CBSA-ICG@HA, which was about 200 nm to easily retain at tumor site and could be degraded by tumor-specific hyaluronidase into small nanoparticles for deep tumor penetration. The HA shell also endowed AuNC@CBSA-ICG@HA with actively targeting ability and hyaluronidase-dependent drug release. Furthermore, the quenching and recovery of fluorescence revealed the interaction between ICG and carrier, which was essential for the investigation of pharmacokinetic profiles. No matter in vitro or in vivo, AuNC@CBSA-ICG@HA showed markedly anti-tumor effect, and could suppress 95.0% of tumor growth on mice breast cancer model. All results demonstrated AuNC@CBSA-ICG@HA was potential for breast cancer therapy. KEY WORDS: Size-shrinkage, Drug release, Photothermal therapy, Theranostic, Breast cancer

Chemotherapy has an essential role not only in advanced solid tumor therapy intervention but also in society’s health at large. Chemoresistance, however, seriously restricts the efficiency and sensitivity of chemotherapeutic agents, representing a significant threat to patients’ quality of life and life expectancy. How to reverse chemoresistance, improve efficacy sensitization response, and reduce adverse side effects need to be tackled urgently. Recently, studies on the effect of ultrasonic microbubble cavitation on enhanced tissue permeability and retention (EPR) have attracted the attention of researchers. Compared with the traditional targeted drug delivery regimen, the microbubble cavitation effect, which can be used to enhance the EPR effect, has the advantages of less trauma, low cost, and good sensitization effect, and has significant application prospects. This article reviews the research progress of ultrasound-mediated microbubble cavitation in the treatment of solid tumors and discusses its mechanism of action to provide new ideas for better treatment strategies.

Biomimetic nanomaterials (BNMs) are functional materials containing nanoscale components and having structural and technological similarities to natural (biogenic) prototypes. Despite the fact that biomimetic approaches in materials technology have been used since the second half of the 20th century, BNMs are still at the forefront of materials science. This review considered a general classification of such nanomaterials according to the characteristic features of natural analogues that are reproduced in the preparation of BNMs, including biomimetic structure, biomimetic synthesis, and the inclusion of biogenic components. BNMs containing magnetic, metal, or metal oxide organic and ceramic structural elements (including their various combinations) were considered separately. The BNMs under consideration were analyzed according to the declared areas of application, which included tooth and bone reconstruction, magnetic and infrared hyperthermia, chemo- and immunotherapy, the development of new drugs for targeted therapy, antibacterial and anti-inflammatory therapy, and bioimaging. In conclusion, the authors’ point of view is given about the prospects for the development of this scientific area associated with the use of native, genetically modified, or completely artificial phospholipid membranes, which allow combining the physicochemical and biological properties of biogenic prototypes with high biocompatibility, economic availability, and scalability of fully synthetic nanomaterials.

Abstract The past decades have witnessed great progress in nanoparticle (NP)‐based brain‐targeting drug delivery systems, while their therapeutic potentials are yet to be fully exploited given that the majority of them are lost during the delivery process. Rational design of brain‐targeting drug delivery systems requires a deep understanding of the entire delivery process along with the issues that they may encounter. Herein, this review first analyzes the typical delivery process of a systemically administrated NPs‐based brain‐targeting drug delivery system and proposes a six‐step CRITID delivery cascade: circulation in systemic blood, recognizing receptor on blood‐brain barrier (BBB), intracellular transport, diseased cell targeting after entering into parenchyma, internalization by diseased cells, and finally intracellular drug release. By dissecting the entire delivery process into six steps, this review seeks to provide a deep understanding of the issues that may restrict the delivery efficiency of brain‐targeting drug delivery systems as well as the specific requirements that may guarantee minimal loss at each step. Currently developed strategies used for troubleshooting these issues are reviewed and some state‐of‐the‐art design features meeting these requirements are highlighted. The CRITID delivery cascade can serve as a guideline for designing more efficient and specific brain‐targeting drug delivery systems.

Due to the ability of the blood–brain barrier (BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood–brain tumor barrier (BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

Heat shock proteins (HSPs) constitute a large family of conserved proteins acting as molecular chaperones that play a key role in intracellular protein homeostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSP families such as small HSPs, HSP40, HSP60, HSP70 and HSP90 have been found to be localized on the plasma membrane of malignantly transformed cells. In the current article, the role of membrane-associated molecular chaperones in normal and tumor cells is comprehensively reviewed with implications of these proteins as plausible targets for cancer therapy and diagnostics.