ROS-Responsive and Self-Tumor Curing Methionine Polymer Library Based Nanoparticles with Self-Accelerated Drug Release and Hydrophobicity/Hydrophilicity Switching Capability for Enhanced Cancer Therapy.

The applications of amino acid-based polymers are impeded by their limited structure and functions. Herein, a small library of methionine-based polymers (Met-P) with programmed structure and reactive oxygen species (ROS)-responsive properties is developed for tumor therapy. The Met-P can self-assemble into sub-100 nm nanoparticles (NPs) and effectively load anticancer drugs (such as paclitaxel (PTX) (P@Met-P NPs)) via the nanoprecipitation method. The screened NPs with superior stability and high drug loading are further evaluated in vitro and in vivo. When encountering with ROS, the Met-P polymers will be oxidized and then switch from a hydrophobic to a hydrophilic state, triggering the rapid and self-accelerated release of PTX. The in vivo results indicated that the screened P@2Met10 NPs possessed significant anticancer performance and effectively alleviated the side effects of PTX. More interestingly, the blank 2Met10 NPs displayed an obvious self-tumor inhibiting efficacy. Furthermore, the other Met-P NPs (such as 2Met8, 4Met8, and 4Met10) are also found to exhibit varied self-anti-cancer capabilities. Overall, this ROS-responsive Met-P library is a rare anticancer platform with hydrophobic/hydrophilic switching, controlled drug release, and self-anticancer therapy capability.

Natural ursolic acid based self-therapeutic polymer as nanocarrier to deliver natural resveratrol for natural therapy of acute kidney injury.

Acute kidney injury (AKI) is a common kidney disease associated with excessive reactive oxygen species (ROS). Unfortunately, due to the low kidney targeting and undesired side effects, the existing antioxidant and anti-inflammatory drugs are unavailable for AKI management in clinic. Therefore, it's essential to develop effective nanodrugs with high renal targeting and biocompatibility for AKI treatment. Herein, we reported a novel nanodrug for AKI treatment, utilizing poly(ursolic acid) (PUA) as a bioactive nanocarrier and resveratrol (RES) as a model drug. The PUA polymer was synthesized form ursolic acid with intrinsic antioxidant and anti-inflammatory activities, and successfully encapsulated RES through a nanoprecipitation method. Subsequently, we systemically investigated the therapeutic potential of RES-loaded PUA nanoparticles (PUA NPs@RES) against AKI. In vitro results demonstrated that PUA NPs@RES effectively scavenged ROS and provided substantial protection against H2O2-induced cellular damage. In vivo studies revealed that PUA NPs significantly improved drug accumulation in the kidneys and exhibited favorable biocompatibility. Furthermore, PUA NPs alone exhibited additional anti-inflammatory and antioxidant effect, synergistically enhancing therapeutic efficacy in AKI mouse models when combined with RES. Overall, our study successfully developed an effective nanodrug using self-therapeutic nanocarriers, presenting a promising option for the treatment of AKI.

Inhaled mRNA nanoparticles dual-targeting cancer cells and macrophages in the lung for effective transfection.

Messenger RNA (mRNA)-based therapeutics are transforming the landscapes of medicine, yet targeted delivery of mRNA to specific cell types while minimizing off-target accumulation remains challenging for mRNA-mediated therapy. In this study, we report an innovative design of a cationic lipid- and hyaluronic acid-based, dual-targeted mRNA nanoformulation that can display the desirable stability and efficiently transfect the targeted proteins into lung tissues. More importantly, the optimized dual-targeted mRNA nanoparticles (NPs) can not only accumulate primarily in lung tumor cells and inflammatory macrophages after inhalation delivery but also efficiently express any desirable proteins (e.g., p53 tumor suppressor for therapy, as well as luciferase and green fluorescence protein for imaging as examples in this study) and achieve efficacious lung tissue transfection in vivo. Overall, our findings provide proof-of-principle evidence for the design and use of dual-targeted mRNA NPs in homing to specific cell types to up-regulate target proteins in lung tissues, which may hold great potential for the future development of mRNA-based inhaled medicines or vaccines in treating various lung-related diseases.

Impact of Poly(Ester Amide) Structure on Properties and Drug Delivery for Prostate Cancer Therapy.

Objective: We aim to develop a polymer library consisting of phenylalanine-based poly(ester amide)s (Phe-PEAs) for cancer therapy and investigate the structure-property relationship of these polymers to understand their impact on the drug delivery efficiency of corresponding nanoparticles (NPs). Impact Statement: Our study provides insights into the structure-property relationship of polymers in NP-based drug delivery applications and offers a potential polymer library and NP platform for enhancing cancer therapy. Introduction: Polymer NP-based drug delivery systems have demonstrated substantial potential in cancer therapy by improving drug efficacy and minimizing systemic toxicity. However, successful design and optimization of these systems require a comprehensive understanding of the relationship between polymer structure and physicochemical properties, which directly influence the drug delivery efficiency of the corresponding NPs. Methods: A series of Phe-PEAs with tunable structures was synthesized by varying the length of the methylene group in the diol part of the polymers. Subsequently, Phe-PEAs were formulated into NPs for doxorubicin (DOX) delivery in prostate cancer therapy. Results: Small adjustments in polymer structure induced the changes in the hydrophobicity and thermal properties of the PEAs, consequently NP size, drug loading capacity, cellular uptake efficacy, and cytotoxicity. Additionally, DOX-loaded Phe-PEA NPs demonstrated enhanced tumor suppression and reduced side effects in prostate tumor-bearing mice. Conclusion: Phe-PEAs, with their finely tunable structures, show great promise as effective and customizable nanocarriers for cancer therapy.

Nanomedicine for the Detection and Treatment of Ocular Bacterial Infections.

Ocular bacterial infection is a prevalent cause of blindness worldwide, with substantial consequences for normal human life. Traditional treatments for ocular bacterial infections areless effective, necessitating the development of novel techniques to enable accurate diagnosis, precise drug delivery, and effective treatment alternatives. With the rapid advancement of nanoscience and biomedicine, increasing emphasis has been placed on multifunctional nanosystems to overcome the challenges posed by ocular bacterial infections. Given the advantages of nanotechnology in the biomedical industry, it can be utilized to diagnose ocular bacterial infections, administer medications, and treat them. In this review, the recent advancements in nanosystems for the detection and treatment of ocular bacterial infections are discussed; this includes the latest application scenarios of nanomaterials for ocular bacterial infections, in addition to the impact of their essential characteristics on bioavailability, tissue permeability, and inflammatory microenvironment. Through an in-depth investigation into the effect of sophisticated ocular barriers, antibacterial drug formulations, and ocular metabolism on drug delivery systems, this review highlights the challenges faced by ophthalmic medicine and encourages basic research and future clinical transformation based on ophthalmic antibacterial nanomedicine.

A Nanovaccine Based on Adjuvant Peptide FK-13 and l-Phenylalanine Poly(ester amide) Enhances CD8+ T Cell-Mediated Antitumor Immunity.

Cancer vaccines have shown promise as effective means of antitumor immunotherapy by inducing tumor antigen-specific T cell immunity. In this study, a novel peptide-based tumor nanovaccine that boosts antigen presentation and elicits effective antitumor immunity is developed. The adjuvant characteristics of an antimicrobial peptide-derived core peptide, FK-13, are investigated and used it to generate a fusion peptide named FK-33 with tumor antigen epitopes. l-phenylalanine-based poly(ester amide) (Phe-PEA), 8p4, is also identified as a competent delivery vehicle for the fusion peptide FK-33. Notably, the vaccination of 8p4 + FK-33 nanoparticles (8FNs) in vivo induces dendritic cell activation in the lymph nodes and elicits robust tumor antigen-specific CD8+ T cell response. The nanovaccine 8FNs demonstrate significant therapeutic and prophylactic efficacy against in situ tumor growth, effectively inhibit tumor metastasis, and significantly prolong the survival of tumor-bearing mice. Moreover, 8FNs can incorporate different tumor antigens and exhibit a synergistic therapeutic effect with antiprogrammed cell death protein 1 (PD-1) therapy. In summary, 8FNs represent a promising platform for personalized cancer vaccines and may serve as a potential combinational modality to improve current immunotherapy.

THQ-Xanthene: An Emerging Strategy to Create Next-Generation NIR-I/II Fluorophores.

Near-infrared fluorescence imaging is vital for exploring the biological world. The short emissions (<650 nm) and small Stokes shifts (<30 nm) of current xanthene dyes obstruct their biological applications since a long time. Recently, a potent and universal THQ structural modification technique that shifts emission to the NIR-I/II range and enables a substantial Stokes shift (>100 nm) for THQ-modified xanthene dyes is established. Thus, a timely discussion of THQ-xanthene and its applications is extensive. Hence, the advent, working principles, development trajectory, and biological applications of THQ-xanthene dyes, especially in the fields of fluorescence probe-based sensing and imaging, cancer theranostics, and super-resolution imaging, are introduced. It is envisioned that the THQ modification tactic is a simple yet exceptional approach to upgrade the performance of conventional xanthene dyes. THQ-xanthene will advance the strides of xanthene-based potentials in early fluorescent diagnosis of diseases, cancer theranostics, and imaging-guided surgery.

Cysteine-Based Redox-Responsive Nanoparticles for Fibroblast-Targeted Drug Delivery in the Treatment of Myocardial Infarction.

Upon myocardial infarction (MI), activated cardiac fibroblasts (CFs) begin to remodel the myocardium, leading to cardiac fibrosis and even heart failure. No therapeutic approaches are currently available to prevent the development of MI-induced pathological fibrosis. Most pharmacological trials fail from poor local drug activity and side effects caused by systemic toxicity, largely due to the lack of a heart-targeted drug delivery system that is selective for activated CFs. Here, we developed a reduced glutathione (GSH)-responsive nanoparticle platform capable of targeted delivering of drugs to activated CFs within the infarct area of a post-MI heart. Compared with systemic drug administration, CF-targeted delivery of PF543, a sphingosine kinase 1 inhibitor identified in a high-throughput antifibrotic drug screening, had higher therapeutic efficacy and lower systemic toxicity in a MI mouse model. Our results provide a CF-targeted strategy to deliver therapeutic agents for pharmacological intervention of cardiac fibrosis.

A Ferroptosis-Inducing and Leukemic Cell-Targeting Drug Nanocarrier Formed by Redox-Responsive Cysteine Polymer for Acute Myeloid Leukemia Therapy.

Ferroptosis is an alternative strategy to overcome chemoresistance, but effective therapeutic approaches to induce ferroptosis for acute myeloid leukemia (AML) treatment are limited. Here, we developed glutathione (GSH)-responsive cysteine polymer-based ferroptosis-inducing nanomedicine (GCFN) as an efficient ferroptosis inducer and chemotherapeutic drug nanocarrier for AML treatment. GCFN depleted intracellular GSH and inhibited glutathione peroxidase 4, a GSH-dependent hydroperoxidase, to cause lipid peroxidation and ferroptosis in AML cells. Furthermore, GCFN-loaded paclitaxel (PTX@GCFN) targeted AML cells and spared normal hematopoietic cells to limit the myeloablation side effects caused by paclitaxel. PTX@GCFN treatment extended the survival of AML mice by specifically releasing paclitaxel and simultaneously inducing ferroptosis in AML cells with restricted myeloablation and tissue damage side effects. Overall, the dual-functional GCFN acts as an effective ferroptosis inducer and a chemotherapeutic drug carrier for AML treatment.

Low dimensional nanomaterials for treating acute kidney injury.

Acute kidney injury (AKI) is one of the most common severe complications among hospitalized patients. In the absence of specific drugs to treat AKI, hemodialysis remains the primary clinical treatment for AKI patients. AKI treatment has received significant attention recently due to the excellent drug delivery capabilities of low-dimensional nanomaterials (LDNs) and their unique therapeutic effects. Diverse LDNs have been proposed to treat AKI, with promising results and the potential for future clinical application. This article aims to provide an overview of the pathogenesis of AKI and the recent advances in the treatment of AKI using different types of LDNs. In addition, it is intended to provide theoretical support for the design of LDNs and implications for AKI treatment.

Natural Soybean Milk-Derived Bioactive Coatings for Enhanced Wound Healing.

Foodborne biomaterials, derived from diets, comprise selfassembled collections of many micro- or nanoscale units with abundant nutrients and active substances. In this study, soybean milk (SBM) was selected as a tissue engineering product for simple and feasible wound repair. SBM is a common drink prepared from soybeans and is rich in soy protein, soy isoflavones, and other bioactive components. Thus, SBM has substantial potential for antioxidation and tissue remodeling. Here, the multifunctional effect of SBM as a bioactive coating for promoting wound healing was studied. The results showed that SBM has good biocompatibility and biological activity. It efficiently scavenges intracellular reactive oxygen species, significantly enhances epithelial cell migration, and improves angiogenesis, thereby accelerating tissue remodeling. The results of animal experiments further confirmed that the SBM-bioinspired coating has promising applications for cutaneous wound regeneration.

Poly(ß-cyclodextrin)/platinum prodrug supramolecular nano system for enhanced cancer therapy: Synthesis and in vivo study.

The use of cisplatin is restricted by systemic toxicity and drug resistance. Supramolecular nano-drug delivery systems involving drugs as building blocks circumvent these limitations promisingly. Herein, we describe a novel supramolecular system [Pt(IV)-SSNPs] based on poly(ß-cyclodextrin), which was synthesized for efficient loading of adamantly-functionalized platinum(IV) prodrug [Pt(IV)-ADA2] via the host-guest interaction between ß-cyclodextrin and adamantyl. Pt(IV)-ADA2 can be converted to active cisplatin in reducing environment in cancer cells, which further reduces systemic toxicity. The introduction of the adamantane group-tethered mPEG2k endowed the Pt(IV)-SSNPs with a longer blood circulation time. In vitro assays exhibited that the Pt(IV)-SSNPs could be uptaken by CT26 cells, resulting in cell cycle arrest in the G2/M and S phases, together with apoptosis. Furthermore, the Pt(IV)-SSNPs showed effective tumor accumulation, better antitumor effect, and negligible cytotoxicity to major organs. These results indicate that supramolecular nanoparticles are a promising platform for efficient cisplatin delivery and cancer treatment.

Development of poly(p-coumaric acid) as a self-anticancer nanocarrier for efficient and biosafe cancer therapy.

Using biocompatible polymers with potential therapeutic activity is an appealing strategy for the development of new functional drug carriers. In this study, we report the synthesis of therapeutic poly(p-coumaric acid) (PCA) from p-coumaric acid, a common plant phenolic acid with multiple bioactivities. The prepared PCA was formulated into nanoparticles (NPs) using the nanoprecipitation method and docetaxel (DTX) was encapsulated to form DTX-loaded PCA NPs (DTX@PCA NPs). Their potential as a nanocarrier for anticancer drug delivery was systematically evaluated. The DTX@PCA NPs not only had a small particle size and good stability, but also exhibited superior in vitro anticancer activity, anti-metastasis ability compared with free drugs, and preferable cellular uptake by tumor cells. In addition, the three-dimensional tumor spheroid assay revealed the effective tumor penetration and anticancer activity of the DTX@PCA NPs. Importantly, the DTX@PCA NPs preferentially accumulated in tumors and prolonged systemic circulation, significantly inhibiting tumor growth in vivo and simultaneously attenuating the side effects of DTX. Interestingly, the blank PCA NPs themselves also exhibited additional tumor suppression activity to some extent with high biosafety, further indicating the significant potential of PCA as a novel self-therapeutic nanocarrier for anticancer drug delivery and enhanced cancer therapy.

Stimuli-responsive cyclodextrin-based supramolecular assemblies as drug carriers.

Cyclodextrins (CDs) are widely employed in biomedical applications because of their unique structures. Various biomedical applications can be achieved in a spatiotemporally controlled manner by integrating the host-guest chemistry of CDs with stimuli-responsive functions. In this review, we summarize the recent advances in stimuli-responsive supramolecular assemblies based on the host-guest chemistry of CDs. The stimuli considered in this review include endogenous (pH, redox, and enzymes) and exogenous stimuli (light, temperature, and magnetic field). We mainly discuss the mechanisms of the stimuli-responsive ability and present typical designs of the corresponding supramolecular assemblies for drug delivery and other potential biomedical applications. The limitations and perspectives of CD-based stimuli-responsive supramolecular assemblies are discussed to further promote the translation of laboratory products into clinical applications.

A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T-Cell Acute Lymphoblastic Leukemia.

Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting-therapy efficacy remains unexplored. Here, an L-phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting myeloid-derived suppressor cells (MDSCs) in T-ALL murine model. Stable-isotope tracer and in vivo drug distribution experiments show that T-ALL cells and MDSCs have enhanced cellular uptake of L-phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN-Dox) specifically targets T-ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN-Dox has reduced cardiotoxicity and myeloablation side effects in treating T-ALL mice. Mechanistically, MRIAN degrades into L-phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T-ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

Advances in Encapsulation and Delivery Strategies for Islet Transplantation.

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic ß-cells in response to autoimmune reactions. Shapiro et al. conducted novel islet transplantation with a glucocorticoid-free immunosuppressive agent in 2000 and achieved great success; since then, islet transplantation has been increasingly regarded as a promising strategy for the curative treatment of T1DM. However, many unavoidable challenges, such as a lack of donors, poor revascularization, blood-mediated inflammatory reactions, hypoxia, and side effects caused by immunosuppression have severely hindered the widespread application of islet transplantation in clinics. Biomaterial-based encapsulation and delivery strategies are proposed for overcoming these obstacles, and have demonstrated remarkable improvements in islet transplantation outcomes. Herein, the major problems faced by islet transplantation are summarized and updated biomaterial-based strategies for islet transplantation, including islet encapsulation across different scales, delivery of stem cell-derived beta cells, co-delivery of islets with accessory cells and immunomodulatory molecules are highlighted.

Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling.

Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.

Redox responsive nanoparticle encapsulating black phosphorus quantum dots for cancer theranostics.

Effective cancer treatment puts high demands for cancer theranostics. For cancer diagnostics, optical coherence tomography (OCT) technology (including photothermal optical coherence tomography (PT-OCT)) has been widely investigated since it induces changes in optical phase transitions in tissue through environmental changes (such as temperature change for PT-OCT). In this report, redox responsive nanoparticle encapsulating black phosphorus quantum dots was developed as a robust PT-OCT agent. Briefly, black phosphorus quantum dots (BPQDs) are incorporated into cysteine-based poly-(disulfide amide) (Cys-PDSA) to form stable and biodegradable nanoagent. The excellent photothermal feature allows BPQD/Cys-PDSA nanoparticles (NPs) as a novel contrast agent for high-resolution PT-OCT bioimaging. The Cys-PDSA can rapidly respond to glutathione and effectively release BPQDs and drugs in vitro and in vivo. And the obtained NPs exhibit excellent near-infrared (NIR) photothermal transduction efficiency and drug delivery capacity that can serve as novel therapeutic platform, with very low chemo drug dosage and side effects. Both of the polymer and BPQD are degradable, indicating this platform is a rare PT-OCT agent that is completely biodegradable. Overall, our research highlights a biodegradable and biocompatible black phosphorus-based nanoagent for both cancer diagnosis and therapy.

Nano and microscale delivery platforms for enhanced oral peptide/protein bioavailability.

In recent years, peptide/protein drugs have attracted considerable attention owing to their superior targeting and therapeutic effect and fewer side effects compared with chemical drugs. Oral administration modality with enhanced patient compliance is increasingly being recognized as an ideal route for peptide/protein delivery. However, the limited permeation efficiency and low oral bioavailability of peptide/protein drugs significantly hinder therapeutic advances. To address these problems, various nano and microscale delivery platforms have been developed, which offer significant advantages in oral peptide/protein delivery. In this review, we briefly introduce the transport mechanisms of oral peptide/protein delivery and the primary barriers to this delivery process. We also highlight the recent advances in various nano and microscale delivery platforms designed for oral peptide/protein delivery. We then summarize the existing strategies used in these delivery platforms to improve the oral bioavailability and permeation efficiency of peptide/protein therapeutics. Finally, we discuss the major challenges faced when nano and microscale systems are used for oral peptide/protein delivery. This review is expected to provide critical insight into the design and development of oral peptide/protein delivery systems with significant therapeutic advances.