pH/H2 O2 Cascade-Responsive Nanoparticles of Lipid-Like Prodrugs through Dynamic-Covalent and Coordination Interactions for Chemotherapy.

Traditional lipid nanoparticles (LNPs) suffer from low drug loading capacity (DLC), weak stability, and lack of responsiveness. Conventional approaches to address these issues involve the synthesis of lipid-prodrug by incorporating responsive covalent linkers. However, such approaches often result in suboptimal sensitivity for drug release and undermine therapeutic effectiveness. Herein, the study reports a fundamentally different concept for designing lipid-like prodrugs through boron-nitrogen (B-N) coordination and dynamic covalent interaction. The 5-fluorouracil-based lipid-like prodrugs, featuring a borate ester consisting of a glycerophosphoryl choline head and a boronic acid-modified 5Fu/dodecanamine complex tail, are used to prepare pH/H2 O2 cascade-responsive LNPs (5Fu-LNPs). The 5Fu-LNPs exhibit enhanced DLC and stability in a neutral physiological environment due to the B-N coordination and enhanced hydrophobicity. In tumors, acidic pH triggers the dissociation of B-N coordination to release prodrugs, which further responds to low H2 O2 concentrations to release drugs, showcasing a potent pH/H2 O2 -cascade-responsive property. Importantly, 5Fu-LNPs demonstrate greater antitumor efficiency and lower toxicity compared to the commercial 5Fu. These results highlight 5Fu-LNPs as a safer and more effective alternative to chemotherapy. This work presents a unique LNP fabrication strategy that can overcome the limitations of conventional LNPs and broaden the range of intelligent nanomaterial preparation techniques.

Monolayer LDH Nanosheets with Ultrahigh ICG Loading for Phototherapy and Ca2+-Induced Mitochondrial Membrane Potential Damage to Co-Enhance Cancer Immunotherapy.

Tumor recurrence and metastasis are the main causes of cancer mortality; traditional chemotherapeutic drugs have severe toxicity and side effects in cancer treatment. To overcome these issues, here, we present a pH-responsive, self-destructive intelligent nanoplatform for magnetic resonance/fluorescence dual-mode image-guided mitochondrial membrane potential damage (MMPD)/photodynamic (PDT)/photothermal (PTT)/immunotherapy for breast cancer treatment with external near infrared (NIR) light irradiation. To do so, we construct multifunctional monolayer-layered double hydroxide (LDH) nanosheets (MICaP), co-loading indocyanine green (ICG) with ultrahigh loading content realized via electrostatic interactions, and calcium phosphate (Ca3(PO4)2) coating via biomineralization. Such a combined therapy design is featured by the outstanding biocompatibility and provokes immunogenic cell death (ICD) of tumors toward cancer immunotherapy. The active transport of excess Ca2+ released from pH-sensitive Ca3(PO4)2 can induce MMPD of tumor cells to minimize oxygen consumption in the tumor microenvironment (TME). The presence of ICG not only generates singlet oxygen (1O2) to induce apoptosis by photodynamic therapy (PDT) but also initiates tumor cell necrosis by photothermal therapy (PTT) under near-infrared (NIR) light radiation. Eventually, the immune response generated by MMPD/PDT/PTT greatly promotes a cytotoxic T lymphocyte (CTL) response that can limit tumor growth and metastasis. Both in vitro and in vivo studies indeed illustrate outstanding antitumor efficiency and outcomes. We anticipate that such precisely designed nanoformulations can contribute in a useful and advantageous way that is conducive to explore novel nanomedicines with notable values in antitumor therapy.

Hydrogel-Forming Microneedles with Applications in Oral Diseases Management.

Controlled drug delivery in the oral cavity poses challenges such as bacterial contamination, saliva dilution, and inactivation by salivary enzymes upon ingestion. Microneedles offer a location-specific, minimally invasive, and retentive approach. Hydrogel-forming microneedles (HFMs) have emerged for dental diagnostics and therapeutics. HFMs penetrate the stratum corneum, undergo swelling upon contact, secure attachment, and enable sustained transdermal or transmucosal drug delivery. Commonly employed polymers such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone are crosslinked with tartaric acid or its derivatives while incorporating therapeutic agents. Microneedle patches provide suture-free and painless drug delivery to keratinized or non-keratinized mucosa, facilitating site-specific treatment and patient compliance. This review comprehensively discusses HFMs' applications in dentistry such as local anesthesia, oral ulcer management, periodontal treatment, etc., encompassing animal experiments, clinical trials, and their fundamental impact and limitations, for example, restricted drug carrying capacity and, until now, a low number of dental clinical trial reports. The review explores the advantages and future perspectives of HFMs for oral drug delivery.

When Iodine Meets Starch: On-Demand Generation of Photothermal Hydrogels for Mild-Temperature Photothermal-Chemo Disinfection.

As an emerging antibacterial strategy, photothermal disinfection attracts increasing attention due to its advantages of high efficacy, wide pertinence, and non-drug resistance. However, the unavoidable shielding of observation by photothermal components and the possible damage to normal tissue caused by hyperthermia restrict its applications. Herein, we propose a composite hydrogel with the ability of on-demand generation of photothermal components and mild-temperature photothermal disinfection by elegantly tuning the binding and release of iodine and starch. The composite hydrogel is obtained by blending iodine-adsorbed pH-responsive ZIF-8 nanoparticles (NPs) with a starch-based hydrogel matrix. Through a convenient pH response, the composite hydrogel leverages the triple functions of iodine, which serves as a disinfectant and reacts with starch to generate a photothermal agent and color indicator, allowing photothermal-chemotherapy combined disinfection on demand. In vitro antibacterial experiments show that the composite hydrogel can respond to the acidification of the microenvironment caused by bacterial metabolism and produce corresponding color changes, realizing naked-eye observation. Meanwhile, under the combined treatment of heating/I2/Zn2+, the composite hydrogel can completely kill Escherichia coli and Staphylococcus aureus at a mild temperature of ∼41 °C. This study represents a breakthrough in on-demand generation of photothermal hydrogels for mild-temperature photothermal disinfection.

Reactive Oxygen Species-Responsive Gel-Based Microneedle Patches for Prolonged and Intelligent Psoriasis Management.

Psoriasis is an inflammatory skin disease. Microneedle (MN) patches can improve psoriasis treatment outcomes by increasing local drug content in the skin. As psoriasis frequently relapses, developing intelligent MN-based drug delivery systems with prolonged therapeutic drug levels and improved treatment efficiency is of great significance. Here, we designed detachable H2O2-responsive gel-based MN patches containing methotrexate (MTX) and epigallocatechin gallate (EGCG) by using EGCG as both cross-linkers for needle-composited materials and anti-inflammatory drugs. The gel-based MNs had dual-mode drug release kinetics, which quickly released MTX diffusively and sustainably released EGCG in an H2O2-responsive way. Compared with dissolving MNs, the gel-based MNs extended skin retention of EGCG, leading to prolonged reactive oxygen species (ROS) scavenging effects. The ROS-responsive MN patches that transdermally delivered antiproliferative and anti-inflammatory drugs improved treatment outcomes in both psoriasis-like and prophylactic psoriasis-like animal models.

Regulating Size and Charge of Liposomes in Microneedles to Enhance Intracellular Drug Delivery Efficiency in Skin for Psoriasis Therapy.

The stratum corneum (SC) and cell membrane are two major barriers that hinder the therapeutic outcomes of transdermal drug delivery for the treatment of skin diseases. While microneedles (MNs) can efficiently penetrate the SC to deliver nanomedicines, the optimization of physicochemical properties of nanomedicines in MNs to enhance their in vivo cellular delivery efficiency remains unclear. Here, how the size and surface charge of drug-loaded liposomes in MNs influence the retention time and cellular delivery in psoriatic skin is systematically investigated. The results indicate that while 100 nm negatively-charged liposomes in MNs show higher cellular uptake in vitro, 250 and 450 nm liposomes could enhance skin retention and the long-term in vivo cellular delivery efficiency of drugs. Moreover, 250 nm cationic liposomes with a stronger positive charge show an extraordinarily long skin retention time of 132 h and significantly higher in vivo cellular internalization. In the treatment study, dexamethasone (dex)-loaded cationic liposomes-integrated MNs show better therapeutic outcomes than dex-loaded anionic liposomes-integrated MNs in a psoriasis-like animal model. The design principles of liposomes in MN drug delivery systems explored in the study hold the potential for enhancing the therapeutic outcomes of psoriasis and are instrumental for successful translation.