Tumor cellular senescence, characterized by reversible cell cycle arrest following anti-cancer therapies, presents a complex paradigm in oncology. Given that senescent tumor cells may promote angiogenesis, tumorigenesis, and metastasis, selective killing senescent cells (SCs)-a strategy termed senotherapy-has emerged as a promising approach to improve cancer treatment. However, the clinical implementation of senotherapy faces significant hurdles, including lack of precise methods for SCs identification and the potential for adverse effects associated with highly cytotoxic senolytic agents. In this account, we elucidate recent advancement in developing novel approaches for the detection and selective elimination of SCs, encompassing prodrugs, nanoparticles, and other cutting-edge drug delivery systems such as PROTAC technology and CAR T cell therapy. Furthermore, we explore the paradoxical nature of SCs, which can induce growth arrest in adjacent neoplastic cells and recruit immunomodulatory cells that contribute to tumor suppression. Therefore, we utilize SCs membrane as vehicles to elicit antitumor immunity and potentially augment existing anti-cancer therapies. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of SCs detection, elimination or utilization.

The tumor microenvironment (TME) emerges as a unique challenge to oncotherapy due to its intricate ecosystem containing diverse cell types, extracellular matrix, secreted factors, and neovascularization, which furnish tumor growth, progression, invasion, and metastasis. Graphene oxide (GO)-based materials have garnered increasing attention in cancer therapy owing to their vast specific surface area, flexible lamellar structure, and electronic-photonic properties. Recently, interactions of GO with the TME have been broadly investigated, including trapping biomolecules, catalysis, cancer stem cell targeting, immunoreactions, etc., which inspires combinative therapeutic strategies to overcome TME obstacles. Herein, we summarize TME features, GO modulating various dimensions of the TME, and a TME-triggerable drug delivery system and highlight innovation and merits in combinative cancer therapy based on TME modulation. This review aims to offer researchers deeper insights into the interactions between versatile GO nanomaterials and the TME, facilitating the development of rational and reliable GO-based nanomedicines for advanced oncotherapy.

Bone metastases and pathological fractures significantly impact the prognosis and quality of life in cancer patients. However, clinical and radiological features alone have been shown to fail to predict skeletal related events of a bone metastasis (SREs).

This study focuses on key molecular players including Matrix Metalloproteinases (MMPs), Integrins, Bone Morphogenetic Proteins (BMPs), Parathormone-related Protein (PTHrP).

The RANK/RANKL/Osteoprotegerin (OPG) pathway, and N-terminal peptide (NTx), involved in the metastatic process and bone integrity disruption. Elevated levels of these molecules have been pointed out as potential biomarkers for predicting SREs, but they have been poorly investigated. Moreover, batimastat, marimastat, tanomastat, andecaliximab, and HIV protease targeting MMPs; Volociximab/M200, cilengitide, abituzumab, and FAK inhibitors targeting integrins; LDN193189, DMH1, and ISLR modulators targeting BMPs; and PTH (7-33)-CBD targeting PTHrP have shown promising results antagonizing these molecules, but no effect on preventing and managing metastatic fractures has been assessed yet.

This paper underscores the importance of advanced molecular biology and transcriptomics in identifying novel therapeutic targets. The integration of these biomarkers with clinical and radiological assessments using artificial intelligence tools could revolutionize the diagnostics and treatment strategies for patients with bone metastases.

β-Galactoside prodrugs, activated by β-galactosidase (β-gal) highly expressed in some cancer cells, have been explored as anticancer agents for three decades. However, the distribution of β-gal lacks sufficient specificity to ensure precise drug release at cancer sites. By utilizing the highly stringent substrate specificity of β-gal, we chose the naturally occurring hydroxyl group of galactose as a prodrug modification site and developed a new class of tandem activated caged galactoside (TACG) prodrugs that require an additional trigger for more controlled on-demand drug release. We demonstrated that attaching various masking groups to the 6-hydroxyl group of galactose renders the galactosides resistant to β-gal hydrolysis. Focusing on the photosensitive mask 4,5-dimethoxy-2-nitrobenzyl (DMNB), we synthesized O6-DMNB modified galactosides of combretastatin A4 and 8-hydroxyquinoline, showcasing their UV/β-gal-dependent anticancer activities. We further established synthetic routes for O2-, O3-, and O4-DMNB modified TACGs. Comparative intracellular studies highlighted the O2-DMNB modified TACG as the most effective positional isomer, offering superior light-dependent selectivity. This insight led to the discovery of the O2-DMNB modified galactoside of combretastatin A4 as a potent UV-dependent microtubule assembly inhibitor. Our work provides a straightforward, effective, and universally applicable strategy for constructing dual-stimulus responsive galactoside prodrugs, extendable to various glycoside prodrugs, advancing carbohydrate-based drug discovery.

During the process of sperm cryopreservation, the overproduction of reactive oxygen species (ROS) triggers oxidative stress thereby leading to a reduction in sperm motility and quality. Therefore, it is a feasible strategy to mitigate oxidative damage during cryopreservation by adding antioxidants to freezing media.

In this study, we explored the potential of melatonin to protect sperm from oxidative stress-induced damage by evaluating sperm-related parameters after thawing through self-assembly with a hyaluronic acid-bilirubin conjugate into nanoparticles (M@HBn).

The optimized M@HBn exhibited uniform spherical morphology with average particle size of 112.57   ±   9.8 nm, PDI of 0.22   ±   0.02, a surface potential of  - 0.43   ±   1.02 mV and entrapment efficiency of 85.1   ±   4.6%. The addition of 5 μM M@HBn demonstrated a notable enhancement in frozen-thawed human spermatozoa viability, motility, and DNA integrity by scavenging ROS. Additionally, the use of M@HBn supplementation in freezing medium resulted in the most mitochondrial stability and total viability as compared to the other groups.

These findings suggest that M@HBn have the potential to serve as a novel drug delivery platform for protecting spermatozoa against from cryodamage while enhancing the quality of cryopreserved sperm and the bioavailability of melatonin.

Each stage of tumor development is intrinsically linked to the tumor microenvironment (TME), wherein the extracellular matrix (ECM) serves as a vital and abundant component in tumor tissues. The ECM is a non-cellular, three-dimensional macromolecular network scaffold that provides structural support to cells, stores bioactive molecules, and mediates signaling pathways through specific binding to cell surface receptors. Moreover, the ECM in tumor tissues plays a crucial role in impeding drug diffusion and resisting apoptosis induced by conventional anti-cancer therapies that primarily target cancer cells. Therefore, directing attentions towards the tumor ECM can facilitate the identification of novel targets and the development of new therapies. This review aims to summarize the composition, structure, remodeling, and function of tumor ECM, its association with drug resistance, and current targeting strategies, with a specific emphasis on nanoparticles (NPs).

Approximately 90% of the lesions of hypophyseal origins are represented by pituitary neuroendocrine tumors, which further account for up to 22.5% of the intracranial tumors in the adult population. Although the intricacy of this pathology is yet to be fully understood on a biomolecular level, it is well known that these lesions develop within a microenvironment that supports their evolution and existence. The role of the tumoral microenvironment in pituitary lesions is pivotal, mainly due to this gland's distinct anatomical, histological, and physiological structure and function. Each component of the tumoral microenvironment is specifically involved in tumorigenesis, angiogenesis, tumoral growth, progression, and dissemination. By recognizing and understanding how these elements are involved in such processes, targeted treatments can emerge, and better future management of pituitary lesions can be provided. This article aims to summarize the role of each component of the tumoral microenvironment in pituitary lesions while assessing their association with biomolecular mechanisms.

Matrix metalloproteinases (MMPs) are key enzymes involved in extracellular matrix (ECM) remodeling, regulating a wide range of cellular and immune processes in both homeostatic and pathological conditions. Host-microbiota interactions play a critical role in maintaining ECM balance; however, during dysbiosis, this regulation is disrupted, leading to compromised barrier integrity, pathogen translocation into circulation, and the development of systemic diseases and cancer. This review highlights the bidirectional relationship between MMP expression/activity and microbiota dysbiosis, emphasizing tissue-specific alterations in MMP activity that contribute to disease progression. In addition, it integrates interdisciplinary evidence to illustrate the MMP-dependent mechanisms underlying various pathologies associated with oral and gut microbiome dysbiosis, including long-range effects through the gut-skin and gut-brain axes. Thus, this review introduces the emerging field of MatrixBiome, which explores the complex interactions between the ECM, microbiota, and host tissues. Finally, it also outlines therapeutic strategies to modulate MMP levels, either indirectly through microbiome-targeted approaches (e.g., prebiotics, probiotics, and postbiotics) or directly using MMP inhibitors, offering promising avenues for future clinical interventions.

Tumor-specific T cells play a crucial role in tumor immunity. However, these cells are often scarce and functionally exhausted within the tumor microenvironment (TME), leading to the limited efficacy of immunotherapy in many cancer patients. In contrast, increasing evidence suggests that the TME is rich in "bystander" T cells (TBYS), most of which are virus-specific and unrelated to the tumor. These TBYS cells retain functional memory characteristics and the potential to kill tumor cells. To utilize TBYS cells in the TME for tumor elimination, we designed an intracellular delivery system, ASCP, encoding a TBYS epitope to redirect tumor cell antigen specificity toward pre-existing TBYS cells, resulting in effective tumor inhibition in multiple preclinical models. The ASCP-antigen peptide strategy restores the antigenicity of tumor cells and induces epitope spreading of tumor antigens, thereby eliciting more diverse tumor-specific T cell responses. Remarkably, this strategy incorporates MHC-II epitopes containing unnatural amino acids (p-nitrophenylalanine, termed NiraTh), which stimulate CD4+ T cell-mediated immunity and assist CD8+ T cells in clearing tumors. Overall, the ASCP-mediated tumor antigen reprogramming strategy provides important insights for cancer immunotherapy in populations with a history of common viral infections.

The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies. Highlighting preclinical successes and ongoing clinical trials, we evaluate the current landscape and potential of these innovative approaches. We also consider future research directions as well as the most important barriers to successful clinical translation, emphasizing the transformative potential of tumour-responsive nanomaterials in overcoming the barriers that limit the activity of traditional immunotherapies, thus improving patient outcomes.

Acute lung injury (ALI) is a life-threatening condition characterized by rapidly progressing respiratory distress and hypoxemia. Oxidative stress-induced inflammation in lung tissue plays a crucial role in the progression of ALI. Excessive generation of reactive oxygen species (ROS) in the pulmonary microenvironment activates inflammatory signaling pathways, enhancing the transcription of pro-inflammatory factors and ultimately leading to tissue necrosis.

Bilirubin (BR), an exceptional endogenous antioxidant, possesses the ability to counteract elevated levels of reactive oxygen species (ROS) through direct reactions or by inducing antioxidant systems such as Nrf2/HO-1 signaling. However, its limited solubility poses a hindrance to further applications. Hence, it is imperative to develop a suitable bilirubin-based system for biological utilization.

In this study, we developed a bilirubin-based ROS-sensitive adaptive nanoscavenger (GP@BR) by co-assembling bilirubin-conjugated glycol chitosan (GC-BR) and bilirubin-conjugated polyethylene glycol (PEG-BR), aiming to alleviate oxidative stress for ALI treatment.

The different conjugations endowed the bilirubin derivatives with varying sensitivity towards reacting with ROS, enabling GP@BR to exert antioxidative properties specifically in oxidative environments on demand. Besides its excellent antioxidant properties, GP@BR also demonstrated the ability to absorb excess inflammatory cytokines. Moreover, our optimized nanoscavenger facilitated bilirubin transport across the mucosal layer on pulmonary epithelial cells. In vivo studies confirmed that GP@BR significantly improved ALI symptoms and suppressed pulmonary fibrosis.

This study highlighted the potential of ROS-sensitive adaptive properties and multiple actions of this nanoscavenger in the treatment of ALI.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world, mainly because of its powerful pro-connective tissue proliferation matrix and immunosuppressive tumor microenvironment (TME), which promote tumor progression and metastasis. In addition, the extracellular matrix leads to vascular collapse, increased interstitial fluid pressure, and obstruction of lymphatic return, thereby hindering effective drug delivery, deep penetration, and immune cell infiltration. Therefore, reshaping the TME to enhance tumor perfusion, increase deep drug penetration, and reverse immune suppression has become a key therapeutic strategy. Traditional therapies for PDAC, including surgery, radiation, and chemotherapy, face significant limitations. Surgery is challenging due to tumor location and growth, while chemotherapy and radiation are hindered by the dense extracellular matrix and immunosuppressive TME. In recent years, the advancement of nanotechnology has provided new opportunities to improve drug efficacy. Nanoscale drug delivery systems (NDDSs) provide several advantages, including improved drug stability in vivo, enhanced tumor penetration, and reduced systemic toxicity. However, the clinical translation of nanotechnology in PDAC therapy faces several challenges. These include the need for precise targeting and control over drug release, potential immune responses to the nanocarriers, and the scalability and cost-effectiveness of production. This article provides an overview of the latest nanobased methods for achieving better therapeutic outcomes and overcoming drug resistance. We pay special attention to TME-targeted therapy in the context of PDAC, discuss the advantages and limitations of current strategies, and emphasize promising new developments. By emphasizing the enormous potential of NDDSs in improving the treatment outcomes of patients with PDAC, while critically discussing the limitations of traditional therapies and the challenges faced by nanotechnology in achieving clinical breakthroughs, our review paves the way for future research in this rapidly developing field.

Embolotherapy is an effective antitumor method, which essentially blocks the oxygen supply and induces hypoxia to treat tumors; however, traditional practices demand high expertise and harbor risks of complications. This study presents a mesoporous polydopamine-based (MPDA) drug delivery platform modified by engineered fusion proteins, which can specifically embolize tumor blood vessels and deliver the hypoxia-activated prodrug tirapazamine (TPZ). The fusion protein consists of an affibody targeting HER-2, a substrate for MMP-2, an RGD tripeptide, and a truncated tissue factor (tTF), which is then connected to MPDA loaded with TPZ. This nanodrug can actively target HER-2, interact with MMP-2 in the tumor microenvironment (TME), and embolize blood vessels; then, under TME acidic circumstances, MPDA releases TPZ, which is activated by hypoxia aggravated by embolization, and kills tumors. This embolization strategy, which is activated only under specific conditions, is extremely safe, and it compensates for the inadequacies of conventional embolization therapy, while also addressing the issue of hypoxia deficiency in hypoxia-activated prodrug therapy.

Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment by promoting tumor growth, immune evasion, and metastasis. Recently, drug delivery systems targeting CAFs have emerged as a promising long-term and effective approach to cancer treatment. Advances in nanotechnology, in particular, have led to the development of nanomedicine delivery systems designed specifically to target CAFs, offering new possibilities for precise and personalized cancer therapies. This article reviews recent progress in drug delivery using nanocarriers that target CAFs. Additionally, we explore the potential of combining multiple therapies, such as chemotherapy and immunotherapy, with nanocarriers to enhance efficacy and overcome drug resistance. Although many preclinical studies show promise, the clinical application of nanomedicine still faces considerable challenges, especially in terms of drug penetration and large-scale production. Therefore, this review aims to provide a fresh perspective on CAF-targeted drug delivery systems and highlight potential future research directions and clinical applications.

Chemoimmunotherapy is an emerging paradigm in the clinic for treating several malignant diseases, such as non-small cell lung cancer, breast cancer, and large B-cell lymphoma. However, the efficacy of this strategy is still restricted by serious adverse events and a high therapeutic termination rate, presumably due to the lack of tumor-targeted distribution of both chemotherapeutic and immunotherapeutic agents. Targeted drug delivery has the potential to address this issue. Among the most promising nanocarriers in clinical translation, liposomes have drawn great attention in cancer chemoimmunotherapy in recent years. Liposomes-enabled cancer chemoimmunotherapy has made significant progress in clinics, with impressive therapeutic outcomes. This review summarizes the latest preclinical and clinical progress in liposome-enabled cancer chemoimmunotherapy and discusses the challenges and future directions of this field.

Acute pancreatitis (AP) is a disease characterized by an acute inflammatory response in the pancreas. This is caused by the abnormal activation of pancreatic enzymes by a variety of etiologic factors, which results in a localized inflammatory response. The symptoms of this disease include abdominal pain, nausea and vomiting and fever. These symptoms are induced by a hyperinflammatory response and oxidative stress. In recent years, research has focused on developing anti-inflammatory and antioxidative therapies for the treatment of acute pancreatitis (AP). However, there are still limitations to this approach, including poor drug stability, low bioavailability and a short half-life. The advent of nanotechnology has opened up a novel avenue for the management of acute pancreatitis (AP). Nanomaterials can serve as an efficacious vehicle for conventional pharmaceuticals, enhancing their targeting ability, improving bioavailability and prolonging their half-life. Moreover, they can also exert a direct therapeutic effect. This review begins by introducing the general situation of acute pancreatitis (AP). It then discusses the pathogenesis of acute pancreatitis (AP) and the current status of treatment. Finally, it considers the literature related to the treatment of acute pancreatitis (AP) by nanomaterials. The objective of this study is to provide a comprehensive review of the existing literature on the use of nanomaterials in the treatment of acute pancreatitis (AP). In particular, the changes in inflammatory markers and therapeutic outcomes following the administration of nanomaterials are examined. This is done with the intention of offering insights that can inform subsequent research and facilitate the clinical application of nanomaterials in the management of acute pancreatitis (AP).

Nanoparticles (NPs) as drug delivery platforms encounter numerous obstacles on their journey from administration to the target site. Often, diametrically opposing particle properties are desirable to overcome biological and physical barriers. Therefore, stimuli-responsive NPs have been developed to allow for specific particle adaptation. In this work, it was demonstrated that NPs can be rendered switchable with respect to their interaction with a receptor through an external chemical stimulus. A combination of the inverse electron-demand Diels-Alder (iEDDA) reaction for subsequent NP functionalization and ectoenzyme-based ligand activation allowed for specific particle tailoring. Building on this, a two-step process for target cell recognition was developed. First, NPs were functionalized with Angiotensin-I (Ang-I) as inactive ligand using iEDDA chemistry. At the target site, the ligand was enzymatically processed to Angiotensin-ll (Ang-II) by cellular ectoenzymes. Ang-ll binds as active ligand to the angiotensin ll type 1 (AT1) receptor on the target cell surface. This enzymatic activation aims to minimize the biological effect of the ligand prior to particle binding, while the NP target cell specificity is increased by a two-step recognition with enzymatic processing and receptor binding.

Breast cancer is a complicated malignancy and is known as the most common cancer in women. Considerable experiments have been devoted to explore the basic impacts of the tumor stroma, particularly the extracellular matrix (ECM) and stromal components, on tumor growth and resistance to treatment. ECM is made up of an intricate system of proteins, glycosaminoglycans, and proteoglycans, and maintains structural support and controls key signaling pathways involved in breast tumors. ECM can block different drugs such as chemotherapy and immunotherapy drugs from entering the tumor stroma. Furthermore, the stromal elements, such as cancer-associated fibroblasts (CAFs), immune cells, and blood vessels, have crucial impacts on tumor development and therapeutic resistance. Recently, promising outcomes have been achieved in using nanotechnology for delivering drugs to tumor stroma and crossing ECM in breast malignancies. Nanoparticles have various benefits for targeting the breast tumor stroma, such as improved permeability and retention, extended circulation time, and the ability to actively target the area. This review covers the latest developments in nanoparticle therapies that focus on breast tumor ECM and stroma. We will explore different approaches using nanoparticles to target the delivery of anticancer drugs like chemotherapy, small molecule drugs, various antitumor products, and other specific synthetic therapeutic agents to the breast tumor stroma. Furthermore, we will investigate the utilization of nanoparticles in altering the stromal elements, such as reprogramming CAFs and immune cells, and also remodeling ECM.

Self-immolative prodrugs have gained significant attention as an innovative approach for targeted cancer therapy. These prodrugs are engineered to release the active anticancer agents in response to specific triggers within the tumor microenvironment, thereby improving therapeutic precision while reducing systemic toxicity. This review focuses on the molecular architecture and design principles of self-immolative prodrugs, emphasizing the role of stimuli-responsive linkers and activation mechanisms that enable controlled drug release. Recent advancements in this field include the development of prodrugs that incorporate targeting moieties for enhanced site-specificity. Moreover, the review discusses the incorporation of targeting moieties to achieve site-specific drug delivery, thereby improving the selectivity of treatment. By summarizing key research from the past five years, this review highlights the potential of self-immolative prodrugs to revolutionize cancer treatment strategies and pave the way for their integration into clinical practice.

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.

Cervical cancer is a leading cause of cancer-related mortality in females worldwide, necessitating urgent solutions for effective treatment. Paclitaxel (PTX), a natural diterpene alkaloid compound, has the ability to inhibit mitosis and induce programmed apoptosis in tumor cells. However, its toxicity and drug resistance limit its efficacy in certain cervical cancer patients. β-elemene (β-ELE) can reverse multidrug resistance by inhibiting ATP-binding cassette transporters, thereby enhancing chemotherapy drug retention. Therefore, we propose a combination therapy using PTX/β-ELE to improve chemotherapy sensitivity. To enhance targeted drug delivery, we developed M1-macrophage-membrane-coated nanoparticles (M1@PLGA/PTX/β-ELE) for co-delivery of PTX&β-ELE. Through both in vitro and in vivo cervical cancer models, we demonstrated that M1@PLGA/PTX/β-ELE effectively suppressed tumor progression and polarization of tumor-associated macrophages. Furthermore, H&E staining confirmed the high therapeutic biosafety of M1@PLGA/PTX/β-ELE as there was no significant damage observed in major organs throughout the entire therapeutic process. Overall, this study presents a targeted biomimetic nanoplatform and combinatorial strategy that synergistically enhances chemosensitivity in malignant tumors.

A series of fluorophores based on the (5-methyl-4-phenylthiazol-2-yl)-3-phenylacrylonitrile (MPTA) core were designed and synthesised for photocaging of amino acids and peptides. The photophysical characteristics of these compounds and their hybrids with biomolecules were thoroughly investigated through a joint experimental, spectral and computational approach. The photorelease ability of the obtained amino acids-MPTA and peptides-MPTA hybrids was studied under various conditions, including different UV irradiation wavelength and power, and solvents. The main reaction products were identified using high-performance liquid chromatography combined with high-resolution mass spectrometry. Photo uncaging kinetics was quantitatively studied using absorption spectroscopy. The mechanism of photorelease of amino acids and peptides was elucidated through quantum mechanical calculations, which were also used for the exploration of photophysical properties of the excited states, and photodissociation energetics quantification. Relationships between the structure of fluorophores and photodissociation characteristics were estimated, and fluorophores with the good uncaging characteristics (biomolecule photoreleasing yield, uncaging rate, and effectiveness) were identified. Cell viability assays using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT showed a low cytotoxicity of the hybrids. Confocal microscopy revealed the easy penetration of the hybrids into living cells and their selective accumulation in the endoplasmic reticulum, lipid droplets and mitochondria, depending on their chemical structure.

The tumor stroma plays a crucial role in tumor progression, and the interactions between the extracellular matrix, tumor cells, and stromal cells collectively influence tumor progression and the efficacy of therapeutic agents. Currently, utilizing components of the tumor stroma for drug delivery is a noteworthy strategy. A number of targeted drug delivery systems designed based on tumor stromal components are entering clinical trials. Therefore, this paper provides a thorough examination of the function of tumor stroma in the advancement of targeted drug delivery systems. One approach is to use tumor stromal components for targeted drug delivery, which includes certain stromal components possessing inherent targeting capabilities like HA, laminin, along with targeting stromal cells homologously. Another method entails directly focusing on tumor stromal components to reshape the tumor stroma and facilitate drug delivery. These drug delivery systems exhibit great potential in more effective cancer therapy strategies, such as precise targeting, enhanced penetration, improved safety profile, and biocompatibility. Ultimately, the deployment of these drug delivery systems can deepen our comprehension of tumor stroma and the advanced development of corresponding drug delivery systems.

In recent decades, cancer has posed a challenging obstacle that humans strive to overcome. While phototherapy and immunotherapy are two emerging therapies compared to traditional methods, they each have their advantages and limitations. These limitations include easy metastasis and recurrence, low response rates, and strong side effects. To address these issues, researchers have increasingly focused on combining these two therapies by utilizing a nano-drug delivery system due to its superior targeting effect and high drug loading rate, yielding remarkable results. The combination therapy demonstrates enhanced response efficiency and effectiveness, leading to a preparation that is highly targeted, responsive, and with low recurrence rates. This paper reviews several main mechanisms of anti-tumor effects observed in combination therapy based on the nano-drug delivery system over the last five years. Furthermore, the challenges and future prospects of this combination therapy are also discussed.

The progression of cancer involves mutations in normal cells, leading to uncontrolled division and tissue destruction, highlighting the complexity of tumor microenvironments (TMEs). Immunotherapy has emerged as a transformative approach, yet the balance between efficacy and safety remains a challenge. Nanoparticles such as polymersomes offer the possibility to precisely target tumors, deliver drugs in a controlled way, effectively modulate the antitumor immunity, and notably reduce side effects. Herein, stimuli-responsive polymersomes, with capabilities for carrying multiple therapeutics, are highlighted for their potential in enhancing antitumor immunity through mechanisms like inducing immunogenic cell death and activating STING (stimulator of interferon genes), etc. The recent progress of utilizing stimuli-responsive polymersomes to reshape the TME is reviewed here. The advantages and limitations to applied stimuli-responsive polymersomes are outlined. Additionally, challenges and future prospects in leveraging polymersomes for cancer therapy are discussed, emphasizing the need for future research and clinical translation.

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach.

Nanomaterials have aroused great interests in drug delivery due to their nanoscale structure, facile modifiability, and multifunctional physicochemical properties. Currently, stimuli-responsive nanomaterials that can respond to endogenous or exogenous stimulus display strong potentials in biomedical applications. In comparison with conventional nanomaterials, stimuli-responsive nanomaterials can improve therapeutic efficiency and reduce the toxicity of drugs toward normal tissues through specific targeting and on-demand drug release at pathological sites. In this review, we summarize the responsive mechanism of a variety of stimulus, including pH, redox, and enzymes within pathological microenvironment, as well as exogenous stimulus such as thermal effect, magnetic field, light, and ultrasound. After that, biomedical applications (e.g., drug delivery, imaging, and theranostics) of stimuli-responsive nanomaterials in a diverse array of common diseases, including cardiovascular diseases, cancer, neurological disorders, inflammation, and bacterial infection, are presented and discussed. Finally, the remaining challenges and outlooks of future research directions for the biomedical applications of stimuli-responsive nanomaterials are also discussed. We hope that this review can provide valuable guidance for developing stimuli-responsive nanomaterials and accelerate their biomedical applications in diseases diagnosis and treatment.

Glioblastoma (GBM) remains the epitome of aggressiveness and lethality in the spectrum of brain tumors, primarily due to the blood-brain barrier (BBB) that hinders effective treatment delivery, tumor heterogeneity, and the presence of treatment-resistant stem cells that contribute to tumor recurrence. Nanoparticles (NPs) have been used to overcome these obstacles by attaching targeting ligands to enhance therapeutic efficacy. Among these ligands, peptides stand out due to their ease of synthesis and high selectivity. This article aims to review single and multiligand strategies critically. In addition, it highlights other strategies that integrate the effects of external stimuli, biomimetic approaches, and chemical approaches as nanocatalytic medicine, revealing their significant potential in treating GBM with peptide-functionalized NPs. Alternative routes of parenteral administration, specifically nose-to-brain delivery and local treatment within the resected tumor cavity, are also discussed. Finally, an overview of the significant obstacles and potential strategies to overcome them are discussed to provide a perspective on this promising field of GBM therapy.

Cancer is a highly heterogeneous disease and remains a global health challenge affecting millions of human lives worldwide. Despite advancements in conventional treatments like surgery, chemotherapy, and immunotherapy, the rise of multidrug resistance, tumor recurrence, and their severe side effects and the complex nature of the tumor microenvironment (TME) necessitates innovative therapeutic approaches. Recently, stimulus-responsive nanomedicines designed to target TME characteristics (e.g., pH alterations, redox conditions, enzyme secretion) have gained attention for their potential to enhance anticancer efficacy while minimizing the adverse effects of chemotherapeutics/bioactive compounds. Among the various nanocarriers, hydrogels are intriguing due to their high-water content, adjustable mechanical characteristics, and responsiveness to external and internal stimuli, making them promising candidates for cancer therapy. These properties make hydrogels an ideal nanocarrier for controlled drug release within the TME. This review comprehensively surveys the latest advancements in the area of stimulus-responsive hydrogels for cancer therapy, exploring various stimuli-responsive mechanisms, including biological (e.g., pH, redox), chemical (e.g., enzymes, glucose), and physical (e.g., temperature, light), as well as dual- or multi-stimuli responsiveness. Furthermore, this review addresses the current developments and challenges in hydrogels in cancer treatment. Our aim is to provide readers with a comprehensive understanding of stimulus-responsive hydrogels for cancer treatment, offering novel perspectives on their development for cancer therapy and other medical applications.

Polymer-drug conjugates and polymer-protein conjugates have been pivotal in the realm of drug delivery systems for over half a century. These polymeric drugs are characterized by the conjugation of therapeutic molecules or functional moieties to polymers, enabling a range of benefits including extended circulation times, targeted delivery, controlled release, and decreased immunogenicity. This review delves into recent advancements and challenges in the clinical translations and preclinical studies of polymer-drug conjugates and polymer-protein conjugates. The design principles and functionalization strategies crucial for the development of these polymeric drugs were explored followed by the review of structural properties and characteristics of various polymer carriers. This review also identifies significant obstacles in the clinical translation of polymer-drug conjugates and provides insights into the directions for their future development. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Silk is a biocompatible and biodegradable material that enables the formation of various morphological forms, including nanospheres. The functionalization of bioengineered silk makes it possible to produce particles with specific properties. In addition to tumor cells, the tumor microenvironment (TME) includes stromal, immune, endothelial cells, signaling molecules, and the extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are overexpressed in TME. We investigated bioengineered spider silks functionalized with MMP-responsive peptides to obtain targeted drug release from spheres within TME. Soluble silks MS12.2MS1, MS12.9MS1, and MS22.9MS2 and the corresponding silk spheres carrying MMP-2 or MMP-2/9 responsive peptides were produced, loaded with doxorubicin (Dox), and analyzed for their susceptibility to MMP-2/9 digestion. Although all variants of functionalized silks and spheres were specifically degraded by MMP-2/9, the MS22.9MS2 nanospheres showed the highest levels of degradation and release of Dox after enzyme treatment. Moreover, functionalized spheres were degraded in the presence of cancer cells releasing MMP-2/9. In the 2D and 3D spheroid cancer models, the MMP-2/9-responsive substrate was degraded and released from spheres when loaded into MS22.9MS2 particles but not into the control MS2 spheres. The present study demonstrated that a silk-based MMP-responsive delivery system could be used for controlled drug release within the tumor microenvironment.

Human heavy chain ferritin (HFn) protein cage has been explored as a nanocarrier for targeted anticancer drug delivery. Here, we introduced a matrix metalloproteinases (MMPs)-cleavable sequence into the DE loop of HFn, creating an MMP-responsive variant, MR-HFn, for localized and extracellular drug release. The crystal structure of MR-HFn revealed that the addition of the MMPs recognition sequence did not affect the self-assembly of HFn but presented a surface-exposed loop susceptible to MMPs cleavage. Biochemical analysis indicated that this engineered protein cage is responsive to MMPs, enabling the targeted release of encapsulated drugs. To evaluate the therapeutic potential of this engineered protein cage, monosubstituted β-carboxy phthalocyanine zinc (CPZ), a type of photosensitizer, was loaded inside this protein cage. The prepared CPZ@MR-HFn showed higher uptake and stronger phototoxicity in MMPs overexpressed tumor cells, as well as enhanced penetration into multicellular tumor spheroids compared with its counterpart CPZ@HFn in vitro. In vivo, CPZ@MR-HFn displayed a higher tumor inhibitory rate than CPZ@HFn under illumination. These results indicated that MR-HFn is a promising nanocarrier for anticancer drug delivery and the MMP-responsive strategy here can also be adapted for other stimuli.

Matrix metalloproteinase-2 (MMP-2)-responsive nanodrug vehicles have garnered significant attention as antitumor drug delivery systems due to the extensive research on matrix metalloproteinases (MMPs) within the tumor extracellular matrix (ECM). These nanodrug vehicles exhibit stable circulation in the bloodstream and accumulate specifically in tumors through various mechanisms. Upon reaching tumor tissues, their structures are degraded in response to MMP-2 within the ECM, resulting in drug release. This controlled drug release significantly increases drug concentration within tumors, thereby enhancing its antitumor efficacy while minimizing side effects on normal organs. This review provides an overview of MMP-2 characteristics, enzyme-sensitive materials, and current research progress regarding their application as MMP-2-responsive nanodrug delivery system for anti-tumor drugs, as well as considering their future research prospects. In conclusion, MMP-2-sensitive drug delivery carriers have a broad application in all kinds of nanodrug delivery systems and are expected to become one of the main means for the clinical development and application of nanodrug delivery systems in the future.

The health of the reproductive system is intricately linked to female fertility and quality of life. There has been a growing prevalence of reproductive system disorders among women, particularly in younger age groups, resulting in significant adverse effects on their reproductive health. Consequently, there is an urgent need for effective treatment modalities. Nanotechnology, as an advanced discipline, provides innovative avenues for managing and treating diseases of the female reproductive system by enabling precise manipulation and regulation of biological molecules and cells. By utilizing nanodelivery systems, drugs can be administered with pinpoint accuracy, leading to reduced side effects and improved therapeutic efficacy. Moreover, nanomaterial imaging techniques enhance diagnostic precision and sensitivity, aiding in the assessment of disease severity and progression. Furthermore, the implementation of nanobiosensors facilitates early detection and prevention of ailments. This comprehensive review aims to summarize recent applications of nanotechnology in the treatment of female reproductive system diseases. The latest advancements in drug delivery, diagnosis, and treatment approaches will be discussed, with an emphasis on the potential of nanotechnology to improve treatment outcomes and overall quality of life.

In clinical practice, drug therapy for cancer is still limited by its inefficiency and high toxicity. For precision therapy, various drug delivery systems, including polymeric micelles self-assembled from amphiphilic polymeric materials, have been developed to achieve tumor-targeting drug delivery. Considering the characteristics of the pathophysiological environment at the drug target site, the design, synthesis, or modification of environmentally responsive polymeric materials has become a crucial strategy for drug-targeted delivery. In comparison to the normal physiological environment, tumors possess a unique microenvironment, characterized by a low pH, high reactive oxygen species concentration, hypoxia, and distinct enzyme systems, providing various stimuli for the environmentally responsive design of polymeric micelles. Polymeric micelles with tumor microenvironment (TME)-responsive characteristics have shown significant improvement in precision therapy for cancer treatment. This review mainly outlines the most promising strategies available for exploiting the tumor microenvironment to construct internal stimulus-responsive drug delivery micelles that target tumors and achieve enhanced antitumor efficacy. In addition, the prospects of TME-responsive polymeric micelles for gene therapy and immunotherapy, the most popular current cancer treatments, are also discussed. TME-responsive drug delivery via polymeric micelles will be an efficient and robust approach for developing clinical cancer therapies in the future.

Nanodrug delivery systems based on tumor microenvironment responses have shown excellent performance in tumor-targeted therapy, given their unique targeting and drug-release characteristics. Matrix metalloproteinases (MMPs) have been widely explored owing to their high specificity and expression in various tumor microenvironments. The design of an enzyme-sensitive nanodelivery system using MMPs as targeted receptors could markedly improve the performance of drug targeting. The current review focuses on the development and application of MMP-responsive drug carriers, and summarizes the classification of single- and multi-target nanocarriers based on their MMP responsiveness. The potential applications and challenges of this nanodrug delivery system are discussed to provide a reference for designing high-performance nanodrug delivery systems.

Among all kinds of anticancer agents, small molecule drugs produce an unsatisfactory therapeutic effect due to the lack of selectivity, notorious drug resistance and side effects. Therefore, researchers have begun to pay extensive attention to macromolecular drugs with high efficacy and specificity. As a plant toxin, gelonin exerts potent antitumor activity via inhibiting intracellular protein synthesis. However, gelonin lacks a translocation domain, and thus its poor cellular uptake leads to low outcomes of antitumor response. Here, tumor acidity and matrix metalloproteinase (MMP) dual-responsive functional gelonin (Trx-PVGLIG-pHLIP-gelonin, TPpG), composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), an MMP-responsive motif PVGLIG hexapeptide and gelonin, was innovatively proposed and biologically synthesized by a gene recombination technique. TPpG exhibited good thermal and serum stability, showed MMP responsiveness and could enter tumor cells under weakly acidic conditions, especially for MMP2-overexpressing HT1080 cells. Compared to low MMP2-expressing MCF-7 cells, TPpG displayed enhanced in vitro antitumor efficacy to HT1080 cells at pH 6.5 as determined by different methods. Likewise, TPpG was much more effective in triggering cell apoptosis and inhibiting protein synthesis in HT1080 cells than in MCF-7 cells. Intriguingly, with enhanced stability and pH/MMP dual responsiveness, TPpG notably inhibited subcutaneous HT1080 xenograft growth in mice and no noticeable off-target side effect was observed. This ingeniously designed strategy aims at providing new perspectives for the development of a smart platform that can intelligently respond to a tumor microenvironment for efficient protein delivery.

Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.

With the increasing and aging of global population, there is a dramatic rise in the demand for implants or substitutes to rehabilitate bone-related disorders which can considerably decrease quality of life and even endanger lives. Though titanium and its alloys have been applied as the mainstream material to fabricate implants for load-bearing bone defect restoration or temporary internal fixation devices for bone fractures, it is far from rare to encounter failed cases in clinical practice, particularly with pathological factors involved. In recent years, smart stimuli-responsive (SSR) strategies have been conducted to functionalize titanium implants to improve bone regeneration in pathological conditions, such as bacterial infection, chronic inflammation, tumor and diabetes mellitus, etc. SSR implants can exert on-demand therapeutic and/or pro-regenerative effects in response to externally applied stimuli (such as photostimulation, magnetic field, electrical and ultrasound stimulation) or internal pathology-related microenvironment changes (such as decreased pH value, specific enzyme secreted by bacterial and excessive production of reactive oxygen species). This review summarizes recent progress on the material design and fabrication, responsive mechanisms, and in vitro and in vivo evaluations for versatile clinical applications of SSR titanium implants. In addition, currently existing limitations and challenges and further prospective directions of these strategies are also discussed.

The past two decades have witnessed a rapid progress in the development of surface charge-reversible nanoparticles (NPs) for drug delivery and diagnosis. These NPs are able to elegantly address the polycation dilemma. Converting their surface charge from negative/neutral to positive at the target site, they can substantially improve delivery of drugs and diagnostic agents. By specific stimuli like a shift in pH and redox potential, enzymes, or exogenous stimuli such as light or heat, charge reversal of NP surface can be achieved at the target site. The activated positive surface charge enhances the adhesion of NPs to target cells and facilitates cellular uptake, endosomal escape, and mitochondrial targeting. Because of these properties, the efficacy of incorporated drugs as well as the sensitivity of diagnostic agents can be essentially enhanced. Furthermore, charge-reversible NPs are shown to overcome the biofilm formed by pathogenic bacteria and to shuttle antibiotics directly to the cell membrane of these microorganisms. In this review, the up-to-date design of charge-reversible NPs and their emerging applications in drug delivery and diagnosis are highlighted.