The challenge and opportunity of gut microbiota-targeted nanomedicine for colorectal cancer therapy.

The gut microbiota is an integral component of the colorectal cancer (CRC) microenvironment and is intimately associated with CRC initiation, progression, and therapeutic outcomes. We reviewed recent advancements in utilizing nanotechnology for modulating gut microbiota, discussing strategies and the mechanisms underlying their design. For future nanomedicine design, we propose a 5I principle for individualized nanomedicine in CRC management.

Targeted Inhibition of Lymphovascular Invasion Formation with CREKA Peptide-Modified Silicasomes to Boost Chemotherapy in Bladder Cancer.

Despite its significant clinical efficacy as a first-line treatment for advanced bladder cancer, cisplatin-based chemotherapy provides a limited benefit for patients with lymphovascular invasion (LVI), which is characterized by the presence of tumor emboli within blood vessels and associated with enhanced cisplatin resistance and metastatic potential. Notably, platelets, a critical component of LVI, hinder the delivery of chemotherapeutic agents to tumors and facilitate metastasis. Consequently, platelet function inhibition holds the potential to disrupt LVI formation, as well as augment the antitumor activity of cisplatin. Herein, we developed a tumor microenvironment-targeted nanodrug with lipid-coated mesoporous silica nanoparticles (silicasomes) that synergistically combines cisplatin with an antiplatelet agent, tirofiban, for bladder cancer treatment. The customized nanodrug can concurrently prevent LVI formation and enhance the chemotherapeutic efficacy without significant adverse effects. This study supports the integration of chemotherapy and antiplatelet therapy via a silicasome-based nanosystem as a highly promising strategy for bladder cancer management.

Engineered P2Y12-Overexpressing Cell-Membrane-Wrapped Nanoparticles for the Functional Reversal of Ticagrelor and Clopidogrel.

Antiplatelet agents, particularly P2Y12 receptor inhibitors, are critical medicines in the prevention and treatment of thrombotic diseases in the clinic. However, their long-term use introduces a significant risk of bleeding in patients with cardiovascular diseases. Whether the bleeding is caused by the drug itself or due to surgical procedures or trauma, the need to rapidly reverse the effects of antiplatelet agents in the circulation is essential; however, no such agents are currently available. To address this need, here we describe a strategy that uses cell-membrane-wrapped nanoparticles (CM-NPs) for the rapid reversal of P2Y12 inhibitors. CM-NPs are fabricated with membranes derived from 293T cells genetically engineered to overexpress the P2Y12 receptor. Our findings support the potential of CM-NPs as a strategy for managing bleeding complications associated with P2Y12 receptor inhibitors, offering an approach to improve the safety in the use of these drugs in clinical settings.

Extracellular Vesicles from Nanomedicine-Trained Intestinal Microbiota Substitute for Fecal Microbiota Transplant in Treating Ulcerative Colitis.

The biosafety concerns associated with fecal microbiota transplant (FMT) limit their clinical application in treating ulcerative colitis (UC). Gut microbiota secrete abundant extracellular vesicles (Gm-EVs), which play a critical role in bacteria-to-bacteria and bacteria-to-host communications. Herein, intestinal microbiota are trained using tea leaf lipid/pluronic F127-coated curcumin nanocrystals (CN@Lp127s), which can maintain stability during transit through the gastrointestinal tract. Compared with FMT, Gm-EVs derived from healthy mice significantly improve treatment outcomes against UC by reducing colonic inflammatory responses, restoring colonic barrier function, and rebalancing intestinal microbiota. Strikingly, Gm-EVs obtained from CN@Lp127-trained healthy mice exhibit a superior therapeutic effect on UC compared to groups receiving FMT from healthy mice, Gm-EVs from healthy mice, and FMT from CN@Lp127-trained healthy mice. Oral administration of Gm-EVs from CN@Lp127-trained healthy mice not only alleviates colonic inflammation, promotes mucosal repair, and regulates gut microbiota but also regulates purine metabolism to decrease the uric acid level, resulting in a robust improvement in the UC. This study demonstrates the UC therapeutic efficacy of Gm-EVs derived from nanomedicine-trained gut microbiota in regulating the immune microenvironment, microbiota, and purine metabolism of the colon. These EVs provide an alternative platform to replace FMT as a treatment for UC.

From bench to bedside: Platelet biomimetic nanoparticles as a promising carriers for personalized drug delivery.

In recent decades, there has been a burgeoning interest in cell membrane coating strategies as innovative approach for targeted delivery systems in biomedical applications. Platelet membrane-coated nanoparticles (PNPs), in particular, are gaining interest as a new route for targeted therapy due to their advantages over conventional drug therapies. Their stepwise approach blends the capabilities of the natural platelet membrane (PM) with the adaptable nature of manufactured nanomaterials, resulting in a synergistic combination that enhances drug delivery and enables the development of innovative therapeutics. In this context, we present an overview of the latest advancements in designing PNPs with various structures tailored for precise drug delivery. Initially, we describe the types, preparation methods, delivery mechanisms, and specific advantages of PNPs. Next, we focus on three critical applications of PNPs in diseases: vascular disease therapy, cancer treatment, and management of infectious diseases. This review presents our knowledge of PNPs, summarizes their advancements in targeted therapies and discusses the promising potential for clinical translation of PNPs.

Unlocking the power of nanomedicine: Cell membrane-derived biomimetic cancer nanovaccines for cancer treatment.

Over the past decades, nanomedicine researchers have dedicated their efforts to developing nanoscale platforms capable of more precisely delivering drug payloads to attack tumors. Cancer nanovaccines are exhibiting a distinctive capability in inducing tumor-specific antitumor responses. Nevertheless, there remain numerous challenges that must be addressed for cancer nanovaccines to evoke sufficient therapeutic effects. Cell membrane-derived nanovaccines are an emerging class of cancer vaccines that comprise a synthetic nanoscale core camouflaged by naturally derived cell membranes. The specific cell membrane has a biomimetic nanoformulation with several distinctive abilities, such as immune evasion, enhanced biocompatibility, and tumor targeting, typically associated with a source cell. Here, we discuss the advancements of cell membrane-derived nanovaccines and how these vaccines are used for cancer therapeutics. Translational endeavors are currently in progress, and additional research is also necessary to effectively address crucial areas of demand, thereby facilitating the future successful translation of these emerging vaccine platforms.

Anti-lymphangiogenesis for boosting drug accumulation in tumors.

The inadequate tumor accumulation of anti-cancer agents is a major shortcoming of current therapeutic drugs and remains an even more significant concern in the clinical prospects for nanomedicines. Various strategies aiming at regulating the intratumoral permeability of therapeutic drugs have been explored in preclinical studies, with a primary focus on vascular regulation and stromal reduction. However, these methods may trigger or facilitate tumor metastasis as a tradeoff. Therefore, there is an urgent need for innovative strategies that boost intratumoral drug accumulation without compromising treatment outcomes. As another important factor affecting drug tumor accumulation besides vasculature and stroma, the impact of tumor-associated lymphatic vessels (LVs) has not been widely considered. In the current research, we verified that anlotinib, a tyrosine kinase inhibitor with anti-lymphangiogenesis activity, and SAR131675, a selective VEGFR-3 inhibitor, effectively decreased the density of tumor lymphatic vessels in mouse cancer models, further enhancing drug accumulation in tumor tissue. By combining anlotinib with therapeutic drugs, including doxorubicin (Dox), liposomal doxorubicin (Lip-Dox), and anti-PD-L1 antibody, we observed improved anti-tumor efficacy in comparison with monotherapy regimens. Meanwhile, this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses. Our work describes a new, clinically transferrable approach to augmenting intratumoral drug accumulation, which shows great potential to address the current, unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk.

Balancing mechanical property and swelling behavior of bacterial cellulose film by in-situ adding chitosan oligosaccharide and covalent crosslinking with γ-PGA.

Bacterial cellulose (BC) is an ideal candidate material for drug delivery, but the disbalance between the swelling behavior and mechanical properties limits its application. In this work, covalent crosslinking of γ-polyglutamic acid (γ-PGA) with the chitosan oligosaccharide (COS) embedded in BC was designed to remove the limitation. As a result, the dosage, time, and batch of COS addition significantly affected the mechanical properties and the yield of bacterial cellulose complex film (BCCF). The addition of 2.25 % COS at the incubation time of 0.5, 1.5, and 2 d increased the Young's modulus and the yield by 5.65 and 1.42 times, respectively, but decreased the swelling behavior to 1774 %, 46 % of that of native BC. Covalent γ-PGA transformed the dendritic structure of BCCF into a spider network, decreasing the porosity and increasing the swelling behavior by 3.46 times. The strategy balanced the swelling behavior and mechanical properties through tunning hydrogen bond, electrostatic interaction, and amido bond. The modified BCCF exhibited a desired behavior of benzalkonium chlorides transport, competent for drug delivery. Thereby, the strategy will be a competent candidate to modify BC for such potential applications as wound dressing, artificial skin, scar-inhibiting patch, and so on.

Biomaterial design for regenerating aged bone: materiobiological advances and paradigmatic shifts.

China's aging demographic poses a challenge for treating prevalent bone diseases impacting life quality. As bone regeneration capacity diminishes with age due to cellular dysfunction and inflammation, advanced biomaterials-based approaches offer hope for aged bone regeneration. This review synthesizes materiobiology principles, focusing on biomaterials that target specific biological functions to restore tissue integrity. It covers strategies for stem cell manipulation, regulation of the inflammatory microenvironment, blood vessel regeneration, intervention in bone anabolism and catabolism, and nerve regulation. The review also explores molecular and cellular mechanisms underlying aged bone regeneration and proposes a database-driven design process for future biomaterial development. These insights may also guide therapies for other age-related conditions, contributing to the pursuit of 'healthy aging'.

A Poly Aptamer Encoded DNA Nanocatcher Informs Efficient Virus Trapping.

Broad-spectrum antiviral platforms are always desired but still lack the ability to cope with the threats to global public health. Herein, we develop a poly aptamer encoded DNA nanocatcher platform that can trap entire virus particles to inhibit infection with a broad antiviral spectrum. Ultralong single-stranded DNA (ssDNA) containing repeated aptamers was synthesized as the scaffold of a nanocatcher via a biocatalytic process, wherein mineralization of magnesium pyrophosphate on the ssDNA could occur and consequently lead to the formation of nanocatcher with interfacial nanocaves decorated with virus-binding aptamers. Once the viruses were recognized by the apatmers, they would be captured and trapped in the nanocaves via multisite synergistic interactions. Meanwhile, the size of nanocatchers was optimized to prevent their cellular uptake, which further guaranteed inhibition of virus infection. By taking SARS-CoV-2 variants as a model target, we demonstrated the broad virus-trapping capability of a DNA nanocatcher in engulfing the variants and blocking the infection to host cells.

Anti-tumor immunotherapy using engineered bacterial outer membrane vesicles fused to lysosome-targeting chimeras mediated by transferrin receptor.

The lysosome-targeting chimera (LYTAC) approach has shown promise for the targeted degradation of secreted and membrane proteins via lysosomes. However, there have been challenges in design, development, and targeting. Here, we have designed a genetically engineered transferrin receptor (TfR)-mediated lysosome-targeting chimera (TfR-LYTAC) that is efficiently internalized via TfR-mediate endocytosis and targets PD-L1 for lysosomal degradation in cultured cells but not in vivo due to short half-life and poor tumor targeting. A delivery platform was developed by fusing TfR-LYTAC to the surface of bacterial outer membrane vesicles (OMVs). The engineered OMV-LYTAC combines PD-1/PD-L1 pathway inhibition with LYTAC and immune activation by bacterial OMVs. OMV-LYTAC significantly reduced tumor growth in vivo. We have provided a modular and simple genetic strategy for lysosomal degradation as well as a delivery platform for in vivo tumor targeting. The study paves the way for the targeting and degradation of extracellular proteins using the TfR-LYTAC system.

Chondrocyte membrane-coated nanoparticles promote drug retention and halt cartilage damage in rat and canine osteoarthritis.

Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we show that poly(lactide-co-glycolic acid) nanoparticles coated in chondrocyte membranes (CM-NPs) were preferentially taken up by rat chondrocytes ex vivo compared with uncoated nanoparticles. Internalization of the CM-NPs was mediated primarily by E-cadherin, clathrin-mediated endocytosis, and micropinocytosis. These CM-NPs adhered to the cartilage ECM in rat knee joints in vivo and penetrated deeply into the cartilage matrix with a residence time of more than 34 days. Simulated synovial fluid clearance studies showed that CM-NPs loaded with a Wnt pathway inhibitor, adavivint (CM-NPs-Ada), delayed the catabolic metabolism of rat and human chondrocytes and cartilage explants under inflammatory conditions. In a surgical model of rat OA, drug-loaded CM-NPs effectively restored gait, attenuated periarticular bone remodeling, and provided chondroprotection against cartilage degeneration. OA progression was also mitigated by CM-NPs-Ada in a canine model of anterior cruciate ligament transection. These results demonstrate the feasibility of using chondrocyte membrane-coated nanoparticles to improve the pharmacokinetics and efficacy of anti-OA drugs.

Disruption of Super-Enhancers in Activated Pancreatic Stellate Cells Facilitates Chemotherapy and Immunotherapy in Pancreatic Cancer.

One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a-PSCs). These a-PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)-seq, Assays for Transposase-Accessible Chromatin (ATAC)-seq, and RNA-seq techniques, this work reveals that super-enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE-associated transcription with JQ1 reverses the activated phenotype of a-PSCs and decreases stromal fibrosis in both orthotopic and patient-derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL-12). In summary, this study not only elucidates the contribution of SEs of a-PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a-PSCs may become a gate-opening strategy that benefits PDAC drug therapy by removing stromal barriers.

Bacteria-derived nanovesicles enhance tumour vaccination by trained immunity.

Trained immunity enhances the responsiveness of immune cells to subsequent infections or vaccinations. Here we demonstrate that pre-vaccination with bacteria-derived outer-membrane vesicles, which contain large amounts of pathogen-associated molecular patterns, can be used to potentiate, and enhance, tumour vaccination by trained immunity. Intraperitoneal administration of these outer-membrane vesicles to mice activates inflammasome signalling pathways and induces interleukin-1ß secretion. The elevated interleukin-1ß increases the generation of antigen-presenting cell progenitors. This results in increased immune response when tumour antigens are delivered, and increases tumour-antigen-specific T-cell activation. This trained immunity increased protection from tumour challenge in two distinct cancer models.

The dynamic role of platelets in cancer progression and their therapeutic implications.

Systemic antiplatelet treatment represents a promising option to improve the therapeutic outcomes and therapeutic efficacy of chemotherapy and immunotherapy due to the critical contribution of platelets to tumour progression. However, until recently, targeting platelets as a cancer therapeutic has been hampered by the elevated risk of haemorrhagic and thrombocytopenic (low platelet count) complications owing to the lack of specificity for tumour-associated platelets. Recent work has advanced our understanding of the molecular mechanisms responsible for the contribution of platelets to tumour progression and metastasis. This has led to the identification of the biological changes in platelets in the presence of tumours, the complex interactions between platelets and tumour cells during tumour progression, and the effects of platelets on antitumour therapeutic response. In this Review, we present a detailed picture of the dynamic roles of platelets in tumour development and progression as well as their use in diagnosis, prognosis and monitoring response to therapy. We also provide our view on how to overcome challenges faced by the development of precise antiplatelet strategies for safe and efficient clinical cancer therapy.

Transient Mild Photothermia Improves Therapeutic Performance of Oral Nanomedicines with Enhanced Accumulation in the Colitis Mucosa.

The treatment outcomes of oral medications against ulcerative colitis (UC) have long been restricted by low drug accumulation in the colitis mucosa and subsequent unsatisfactory therapeutic efficacy. Here, high-performance pluronic F127 (P127)-modified gold shell (AuS)-polymeric core nanotherapeutics loading with curcumin (CUR) is constructed. Under near-infrared irradiation, the resultant P127-AuS@CURs generate transient mild photothermia (TMP; ≈42 °C, 10 min), which facilitates their penetration through colonic mucus and favors multiple cellular processes, including cell internalization, lysosomal escape, and controlled CUR release. This strategy relieves intracellular oxidative stress, improves wound healing, and reduces immune responses by polarizing the proinflammatory M1-type macrophages to the anti-inflammatory M2-type. Upon oral administration of hydrogel-encapsulating P127-AuS@CURs plus intestinal intralumen TMP, their therapeutic effects against acute and chronic UC are demonstrated to be superior to those of a widely used clinical drug, dexamethasone. The treatment of P127-AuS@CURs (+ TMP) elevates the proportions of beneficial bacteria (e.g., Lactobacillus and Lachnospiraceae), whose metabolites can also mitigate colitis symptoms by regulating genes associated with antioxidation, anti-inflammation, and wound healing. Overall, the intestinal intralumen TMP offers a promising approach to enhance the therapeutic outcomes of noninvasive medicines against UC.

Biomimetic and bioinspired nano-platforms for cancer vaccine development.

The advent of immunotherapy has revolutionized the treating modalities of cancer. Cancer vaccine, aiming to harness the host immune system to induce a tumor-specific killing effect, holds great promises for its broad patient coverage, high safety, and combination potentials. Despite promising, the clinical translation of cancer vaccines faces obstacles including the lack of potency, limited options of tumor antigens and adjuvants, and immunosuppressive tumor microenvironment. Biomimetic and bioinspired nanotechnology provides new impetus for the designing concepts of cancer vaccines. Through mimicking the stealth coating, pathogen recognition pattern, tissue tropism of pathogen, and other irreplaceable properties from nature, biomimetic and bioinspired cancer vaccines could gain functions such as longstanding, targeting, self-adjuvanting, and on-demand cargo release. The specific behavior and endogenous molecules of each type of living entity (cell or microorganism) offer unique features to cancer vaccines to address specific needs for immunotherapy. In this review, the strategies inspired by eukaryotic cells, bacteria, and viruses will be overviewed for advancing cancer vaccine development. Our insights into the future cancer vaccine development will be shared at the end for expediting the clinical translation.

Tumor-Targeted Delivery of IL-2 by Fusing with a pH Low Insertion Peptide for Antitumor Immunotherapy.

As a pleiotropic cytokine, interleukin-2 (IL-2) can effectively regulate lymphocyte proliferation, survival, and active antitumor immune responses in tumor microenvironments. Although the ability of IL-2 to boost immune responses was reported in cancer patients, its short circulating half-life and high toxicity hinder its broad and continual clinical application. Herein, we developed a novel tumor target agent by fusing pH low insertion peptides (pHLIP) with IL-2, forming the fusion protein pHLIP-IL2. Based on the low pH insertion property of pHLIP, the pHLIP-IL2 fusion protein could be selectively delivered to the acidic tumor microenvironments and then promote the proliferation of killer immune cells to elicit tumor regression. We found that pHLIP-IL2 fusion proteins can be significantly enriched in tumor tissues and can effectively reduce tumor size in diverse tumor models, including breast cancer and melanoma, without apparent adverse effects. These data suggest that the pHLIP-IL2 fusion protein may be a promising solution for the continual and extensive application of IL-2, and pHLIP-IL2 is a potential and valuable therapeutic drug for cancer patients with antitumor immunotherapy.

Ultrasound-Sensitive Intelligent Nanosystems: A Promising Strategy for the Treatment of Neurological Diseases.

Neurological diseases are a major global health challenge, affecting hundreds of millions of people worldwide. Ultrasound therapy plays an irreplaceable role in the treatment of neurological diseases due to its noninvasive, highly focused, and strong tissue penetration capabilities. However, the complexity of brain and nervous system and the safety risks associated with prolonged exposure to ultrasound therapy severely limit the applicability of ultrasound therapy. Ultrasound-sensitive intelligent nanosystems (USINs) are a novel therapeutic strategy for neurological diseases that bring greater spatiotemporal controllability and improve safety to overcome these challenges. This review provides a detailed overview of therapeutic strategies and clinical advances of ultrasound in neurological diseases, focusing on the potential of USINs-based ultrasound in the treatment of neurological diseases. Based on the physical and chemical effects induced by ultrasound, rational design of USINs is a prerequisite for improving the efficacy of ultrasound therapy. Recent developments of ultrasound-sensitive nanocarriers and nanoagents are systemically reviewed. Finally, the challenges and developing prospects of USINs are discussed in depth, with a view to providing useful insights and guidance for efficient ultrasound treatment of neurological diseases.