Cationic lipids play a pivotal role in developing novel drug delivery systems for diverse biomedical applications, owing to the success of mRNA vaccines against COVID-19 and the Phase III antitumor agent EndoTAG-1. However, the therapeutic potential of these positively charged liposomes is limited by dose-dependent toxicity. While an increased content of cationic lipids in the formulation can enhance the uptake and cytotoxicity toward tumor-associated cells, it is crucial to balance these advantages with the associated toxic side effects. In this work, we synthesized the cationic lipid HC-Y-2 and incorporated it into sialic acid (SA)-modified cationic liposomes loaded with paclitaxel to target tumor-associated immune cells efficiently. The SA-modified cationic liposomes exhibited enhanced binding affinity toward both RAW264.7 cells and 4T1 tumor cells in vitro due to the increased ratios of cationic HC-Y-2 content while effectively inhibiting 4T1 cell lung metastasis in vivo. By leveraging electrostatic forces and ligand-receptor interactions, the SA-modified cationic liposomes specifically target malignant tumor-associated immune cells such as tumor-associated macrophages (TAMs), reduce the proportion of cationic lipids in the formulation, and achieve dual objectives: high cellular uptake and potent antitumor efficacy. These findings highlight the potential advantages of this innovative approach utilizing cationic liposomes.

Nanoparticles (NPs) have been designed for the treatment of tumors increasingly. However, the drawbacks of single-size NPs are still worth noting, as their circulation and metabolism in the blood are negatively correlated with their accumulation at the tumor site. If the size of single-size NPs is too small, it will be quickly cleared in the blood circulation, while, the size is too large, the distribution of NPs in the tumor site will be reduced, and the widespread distribution of NPs throughout the body will cause systemic toxicity. Therefore, a class of variable-size NPs with metal organic frameworks (MOFs) as the main carrier, and size conversion in compliance with the characteristics of the tumor microenvironment (TME), was designed. MOF-based variable-size NPs can simultaneously extend the time of blood circulation and metabolism, then enhance the targeting ability of the tumor site. In this review, MOF NPs are categorized and exemplified from a new perspective of NP size variation; the advantages, mechanisms, and significance of MOF-based variable-size NPs were summarized, and the potential and challenges in delivering anti-tumor drugs and multimodal combination therapy were discussed.

In this work, copper nanoclusters (CuNCs) with tiny particle sizes were successfully obtained by a templateassisted synthesis approach. The interfacial interaction energies of cysteine (Cys) and CuNCs were simulated and calculated by molecular dynamics using the Materials Studio program package, and the anchoring sites of Cys on CuNCs surface in aqueous solution were investigated in detail by adsorption modeling. Chitosan (CS), a natural polymer, was used as a confining agent to enhance the excellent peroxidase (POD)-like activity of CuNCs. Therefore, the composite can catalyze the decomposition of hydrogen peroxide (H2O2) to generate hydroxyl radical (& sdot;OH) and possess higher antibacterial activity. A broad-spectrum antibacterial system based on CS@CuNCs was established for E. coli and S. aureus, avoiding the harmful effects of high concentration of H2O2 on organisms. In addition, a cascade reaction with glucose oxidase (GOx) was established for the specific consumption of glucose by bacteria, and a method for the visual colorimetric detection of bacterial viability within 30 min was established. Finally, based on the polymer properties of CS, a cling wrap with antibacterial properties was also prepared for food preservation. In summary, this study provides innovative proposals for the application of CS/nanocluster composite in food packaging, food safety, and even bioengineering.

Immunosuppressive tumor microenvironment (ITM), poor immunogenicity, and low tumor penetration markedly reduce the capability of tumor immunotherapy. To address these challenges, we successfully engineered acidity-triggered nanoparticles (NPs) with size reduction and charge switchable features to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD). The NPs significantly augmented tumor penetrating ability and improved cellular uptake via the detachment of 2,3-dimethylmaleic anhydride-grafted poly(ethylene glycol)-poly(L-lysine) copolymer (mPEG-PLL-DMA, PLM) from large-sized NPs with a negative charge. Subsequently, the NPs with a positive charge and small size rapidly escaped from the lysosomes and released mitoxantrone (MIT) and IDO1 siRNA. The antitumor immune response of IDO1 siRNA and MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. In summary, the results demonstrated that charge-switchable NPs based on the blockage of the IDO1 pathway and ICD activation induce an efficient antitumor immune response, thus showing high potential for treating primary/distant tumors and reducing metastasis. STATEMENT OF SIGNIFICANCE: Acidity-triggered nanoparticles (NPs) with size reduction and charge reversal to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD) were engineered. NPs augmented tumor penetrating ability and improved cellular uptake through the detachment of mPEG-PLL-DMA (PLM) from the large-sized MIT/siR-PLM/PPA NPs with negative charge to expose miniature and positively charged MIT/siR-PPA NPs. The NPs rapidly escaped from the lysosome and sequentially released mitoxantrone (MIT) and IDO1 siRNA. The antitumor synergistic effect of inhibiting the IDO1 pathway by IDO1 siRNA and inducing ICD by MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. Thus, the NPs showed a promising pathway against aggressive and difficult-to-treat cancers.

Multiple biological barriers and tumor metastasis severely impede the tumor therapy. To address these adversities, an acid-activated poly (ethylene glycol)-poly-l-lysine-2,3-dimethylmaleic anhydride/poly (ε-caprolactone)-poly(l-arginine)/β-lapachone nanoparticles (mPEG-PLL-DMA/PCL-P(L-arg)/β-Lap, PLM/PPA/β-Lap NPs) were constructed with charge-reversal and size-reduction for β-Lap delivery with a cascade reaction of reactive oxygen species (ROS) and nitric oxide (NO) production. The nanosystem exhibited highly penetrable, superior cellular uptake and desirable endo-lysosomal escape thanks to size-reduction, charge-reversal and proton sponge, respectively. The vast bulk of ROS, which rapidly generated from β-Lap under high concentration quinone oxidoreductase 1 (NQO1), catalyzed guanidine groups to produce NO and generated highly toxic peroxynitrite (ONOO-). ONOO- would activate pro-matrix metalloproteinases (pro-MMPs) to generate MMPs, degrade the dense extracellular matrix (ECM) to augment the penetration capability, and aggravate DNA damage. NO and ONOO- influenced mitochondrial function by decreasing mitochondrial membrane potential and prevented the production of adenosine triphosphate (ATP), which inhibited the ATP-dependent tumor-derived microvesicles (TMVs) and restrained tumor metastasis. NO was defined as an epithelial mesenchymal transition (EMT) inhibitor to restrain tumor metastasis. All consequences demonstrated that PLM/PPA/β-lap NPs exhibited efficient penetration capability, outstanding anti-metastasis activity and favorable antitumor efficacy. Those novel acid-activated NPs are intended to provide further inspiration for multifunctional NO gas therapy.

肿瘤免疫治疗存在两个严重障碍:①免疫抑制肿瘤微环境(immunosuppressive tumor microenvironment,ITM)和肿瘤的低免疫原性的存在,严重降低肿瘤的免疫应答;②致密而复杂的病理生理屏障严重限制了实体瘤的深部给药.化疗药物多柔比星(doxorubicin,DOX)诱导的肿瘤免疫原性细胞死亡(immunogenic cell death,ICD)是增强肿瘤免疫活性的有效方法.但是ICD作用后细胞毒性T淋巴细胞(cytotoxic T lymphocyte,CTL)分泌的干扰素-γ (interferon-γ,IFN-γ)会增加吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase 1,IDO1)蛋白的表达,其能够增强ITM.而IDO1 siRNA的协同作用会降低IDO1蛋白的表达,调节肿瘤免疫抑制微环境,调节ITM,从而增强DOX的ICD作用.本文利用pH敏感材料PLD [poly(ethylene glycol)-poly-L-lysine-2,3-dimethylmaleic anhydride,mPEG-PLL-DMA]和聚酰胺-胺树状大分子(PAMAM)树状聚合物,一种新型电荷转换、粒径减小的纳米粒,实现肿瘤组织的深层递送.从而使共包载DOX药物和IDO1 siRNA的载体实现高效的肿瘤免疫治疗.制剂及细胞水平的实验表明PLD材料具有显著的pH敏感性.体外3D肿瘤渗透实验结果表明pH敏感材料PLD的加入显著提高制剂的渗透性.此外,建立BALB/c小鼠4T1药效实验模型,动物实验操作过程依照沈阳药科大学动物实验伦理委员会的要求执行.体内的药效实验及组织实验表明,IDO1 siRNA的加入显著提高DOX的ICD作用,从而显著抑制肿瘤生长.

In cancer therapy, it is acknowledged that large-size nanoparticles stay in the circulation system for a long time, but their permeability to tumor tissues is poor. To address the conflicting need for prolonging circulation time and favorable tumor tissue penetration ability, a charge conversional multifunctional nanoplatform was strategically designed to improve the efficacy of small interfering RNA (siRNA) therapy against nonsmall cell lung cancer (NSCLC). The development of nanodrug delivery systems (NDDSs) was constructed by loading siRNA on polyamidoamine (PAMAM) dendrimers to build small-sized PAM/siRNA via electrostatic interaction and then capped with a pH-triggered copolymer poly(ethylene glycol) methyl ether (mPEG)-poly-l-lysine (PLL)-2,3-dimethylmaleic anhydride (DMA) (shorted as PLM) under physiological conditions. While in the tumor microenvironment, the acidic reaction of the PLM copolymer changes from negative charge to positive charge due to the cleavable amide bond between mPEG-PLL and DMA, leading to large-size nanoparticles (NPs) with a negative charge that turns into a positive charge and small NPs with a high tumor-penetrating ability. All of the in vitro and in vivo studies validated that PLM/PAM/siRNA NPs possess desirable features including excellent biocompatibility, a prolonged circulation time, significant pH sensitivity, high tumor tissue penetration ability, and sufficient endo-/lysosomal escape. Taken together, all results suggest tremendous potential of the gene therapy based on the stimuli-sensitive PLM/PAM/siRNA NPs, providing a profound application prospective treatment strategy in cancer gene therapy.

For drug nanocrystals (NCs), particle shapes can affect aqueous solubility, dissolution rate and oral bioavailability. However, the effects of particle shapes on the transport of NCs across the intestinal barriers remain unclear. In the present study, spherical, rod-shaped and flaky NCs (SNCs, RNCs, and FNCs) were prepared and characterized. Meanwhile, fluorescence resonance energy transfer molecules were used to track the fate of intact NCs. Results showed that particle shapes had great influences on the mucus permeation, cellular uptake and transmembrane transport of NCs, and RNCs exhibited the best absorption efficiency. Besides, we found that endoplasmic reticulum/Golgi and Golgi/plasma membrane pathways might be involved in the transcytosis and exocytosis of NCs. Moreover, the oral bioavailability study showed that AUC0-24h of RNCs was 1.44-fold and 1.8-fold higher than that of SNCs and FNCs, respectively. Collectively, these results provided compelling evidences that RNCs could potentially improve the absoption efficacy of NCs in oral delivery. Our findings give deep insights into the impacts of particle shapes on the oral absoption of NCs and provide valuable knowledge for rational design of optimized NCs for oral drug delivery.

Breast cancer is associated with high mortality due to tumor metastasis. The anti-metastasis efficacy of photochemotherapy is strictly limited by poor targeting capability with respect to circulating tumor cells (CTCs) in blood and lymph. Herein, we decorate the platelet membrane (PM) on a surface of nanoparticles (NPs), referred to as nanoplatelets. A chemotherapeutic drug, doxorubicin (DOX), and an FDA-approved photothermal agent, indocyanine green (ICG), are co-encapsulated into the biomimetic nanoplatelets. Nanoplatelets possess immune surveillance-escaping capability and specifically capture and clear CTCs in both blood and lymphatic circulations via high-affinity interactions between the P-Selectin of PM and CD44 receptors of tumor cells. PM-coated NPs show greater cellular uptake in MDA-MB-231 breast cancer cells and further elicit higher cytotoxicity to tumor cells relative to uncoated NPs. In vivo, we disclose that the multifunctional nanoplatelets not only completely ablate the primary tumor but also inhibit breast cancer metastasis with high efficiency in the three established xenograft or orthotopic breast tumor-bearing mice models. We conclude that such biomimetic nanoplatelets represent a promising strategy of coating a surface of nanoparticles with platelet membrane to actively capture and destroy CTCs in blood and lymph in breast cancer anti-metastasis therapy.

Although environment-sensitive prodrug-based nanoparticles (NPs) have developed rapidly, lots of prodrug NPs still show poor selectivity and efficiency of parent drug bioactivation because of tumor heterogeneity. Herein, self-strengthened bioactivating prodrug-based NPs are fabricated via co-encapsulation of oxidation-responsive thioether-linked linoleic acid-paclitaxel conjugates (PTX-S-LA) and β-lapachone (LPC) into polymeric micelles (PMs). Following cellular uptake, PMs first release LPC to significantly elevate the reactive oxidative species (ROS) level through NAD(P)H: quinone oxidoreductase-1 (NQO1) catalysis. Then, NQO1-generated ROS in combination with endogenous high ROS levels in tumor cells could synergistically facilitate PTX-S-LA to release the active cytotoxic agent PTX. Such a novel prodrug nanosystem exhibits self-strengthened prodrug bioactivation, ultraselective release, and cytotoxicity between cancer and normal cells, prolonged circulation time, and enhanced tumor accumulation, leading to high antitumor efficiency and superior biosafety. Our findings pave the new way for the rational design of oxidation-responsive prodrug NPs for high-efficacy cancer chemotherapy.

The aim of the study was to develop a method for the determination of entrapment efficiency of gefitinib liposomes and calculate its transmembrane activation energy. Gefitinib liposomes were prepared with ammonium sulfate gradient method. Ultraviolet spectrophotometry was applied to analyze the amount of intraliposomal gefitinib after separating free drug from liposomes by cation exchange resin. The interactions of gefitinib with empty liposomes or cation exchange resin were investigated, and the transmembrane activation energy of gefitinib was calculated. The average entrapment efficiency of gefitinib liposomes was 92.9%. Gefitinib could be loaded into liposomes taking advantage of the ammonium gradient formed in the course of physical mixing with the transmembrane activation energy of 54.86 kJ/mol, which shows gefitinib has a strong transmembrane ability. The method of cation exchange resin separation-ultraviolet spectrophotometry is simple, rapid and accurate, and it can be used to quantify the entrapment efficiency and transmembrane activation energy of liposomal gefitinib.

Bifunctional composite nanoparticles with simultaneous response toward light excitation and external magnetic field are fabricated by electrostatic adsorption of a single layer of conjugated polyelectrolytes on the magnetic nanoparticle surfaces Cell imaging is realized through incubation of the composite nanoparticles with human hepatoma cell Bel-7402 Both fluorescence microscopy imaging and flow cytometry analysis verify that the bifunctional nanoparticles efficiently penetrate the cell membranes Transmission electron microscopy reveals that the nanoparticles are confined in the endosome and show clear signs of particle aggregation The cellular uptake efficiencies of the magnetic fluorescent nanoparticles can be enhanced greatly by a magnetic field In vitro cell viability results indicate low cytotoxicity of the nanoparticles even after 72 h incubation The current method of fluorescence labeling of nanomaterials by electrostatic adsorption is applicable to a variety of charged nanomaterials that exist with great diversity in chemistry and morphology, which is necessary for estimation of cell toxicity and fundamental understanding of phenomena related to the development of nanomaterial based diagnostics and therapeutics