Engineered Multifunctional Albumin‐Decorated Porous Silicon Nanoparticles for FcRn Translocation of Insulin

The last decade has seen remarkable advances in the development of drug delivery systems as alternative to parenteral injection‐based delivery of insulin. Neonatal Fc receptor (FcRn)‐mediated transcytosis has been recently proposed as a strategy to increase the transport of drugs across the intestinal epithelium. FcRn‐targeted nanoparticles (NPs) could hijack the FcRn transcytotic pathway and cross the epithelial cell layer. In this study, a novel nanoparticulate system for insulin delivery based on porous silicon NPs is proposed. After surface conjugation with albumin and loading with insulin, the NPs are encapsulated into a pH‐responsive polymeric particle by nanoprecipitation. The developed NP formulation shows controlled size and homogeneous size distribution. Transmission electron microscopy (TEM) images show successful encapsulation of the NPs into pH‐sensitive polymeric particles. No insulin release is detected at acidic conditions, but a controlled release profile is observed at intestinal pH. Toxicity studies show high compatibility of the NPs with intestinal cells. In vitro insulin permeation across the intestinal epithelium shows approximately fivefold increase when insulin is loaded into FcRn‐targeted NPs. Overall, these FcRn‐targeted NPs offer a toolbox in the development of targeted therapies for oral delivery of insulin.     

Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

Facile and Scalable Synthesis of Novel Spherical Au Nanocluster Assemblies@Polyacrylic Acid/Calcium Phosphate Nanoparticles for Dual‐Modal Imaging‐Guided Cancer Chemotherapy

Engineering novel theranostic agents with both imaging and therapeutic functions have profound impact on molecular diagnostics, imaging, and therapeutics. In this paper, we develop for the first time a simple, scalable, and reproducible route to synthesize novel multifunctional spherical Au nanoclusters assemblies encapsulated by a polyacylic acid (PAA)/calcium phosphate (CaP) shell with aggregation enhanced fluorescence property (designated as AuNCs‐A@PAA/CaP). Furthermore, the resulting AuNCs‐A@PAA/CaP nanoparticles (NPs) possess a high payload of doxorubicin as synergetic pH‐sensitive drug delivery vehicles to employ for dual‐modal computed tomography (CT) and fluorescence imaging‐guided liver cancer chemotherapy in vivo. The results reveal that AuNCs‐A@PAA/CaP NPs not only provide excellent bimodal CT and fluorescence contrast imaging but also present efficient tumor ablation under the guidance of CT and fluorescence imaging, to achieve excellent chemotherapeutic efficacy to the hepatocarcinoma cell line (H‐22) bearing mice through intravenous injection. Comprehensive blood tests and careful histological examinations reveal no apparent toxicity of AuNCs‐A@PAA/CaP NPs. Our work highlights the great promise of AuNCs‐A@PAA/CaP NPs for guiding and monitoring the chemotherapeutic process using simultaneous dual‐modality CT and fluorescence imaging through a single theranostic agent.     

Targeted Drug Delivery to Stroke via Chemotactic Recruitment of Nanoparticles Coated with Membrane of Engineered Neural Stem Cells

Cell membrane coating has recently emerged as a promising biomimetic approach to engineering nanoparticles (NPs) for targeted drug delivery. However, simple cell membrane coating may not meet the need for efficient drug delivery to the brain. Here, a novel molecular engineering strategy to modify the surface of NPs with a cell membrane coating for enhanced brain penetration is reported. By using poly(lactic‐co‐glycolic) acid NPs as a model, it is shown that delivery of NPs to the ischemic brain is enhanced through surface coating with the membrane of neural stem cells (NSCs), and the delivery efficiency can be further increased using membrane isolated from NSCs engineered for overexpression of CXCR4. It is found that this enhancement is mediated by the chemotactic interaction of CXCR4 with SDF‐1, which is enriched in the ischemic microenvironment. It is demonstrated that the resulting CXCR4‐overexpressing membrane‐coated NPs, termed CMNPs, significantly augment the efficacy of glyburide, an anti‐edema agent, for stroke treatment. The study suggests a new approach to improving drug delivery to the ischemic brain and establishes a novel formulation of glyburide that can be potentially translated into clinical applications to improve management of human patients with stroke.     

Key Role of Microtubule and Its Acetylation in a Zinc Oxide Nanoparticle–Mediated Lysosome–Autophagy System

Autophagy is a biological process that has attracted considerable attention as a target for novel therapeutics. Recently, nanomaterials (NMs) have been reported to modulate autophagy, which makes them potential agents for the treatment of autophagy‐related diseases. In this study, zinc oxide nanoparticles (ZNPs) are utilized to evaluate NM‐induced autophagy and debate the mechanisms involved. It is found that ZNPs undergo pH‐dependent ion shedding and that intracellular zinc ions (Zn²⁺) play a crucial role in autophagy. Autophagy is activated with ZNPs treatment, which is inhibited after Zn²⁺ sequestration via ethylenediamine tetra‐acetic acid. Lysosome‐based autophagic degradation is halted after ZNPs treatment for more than 3 h and is accompanied by blockage of lysophagy, which renews impaired lysosomes. Furthermore, the microtubule (MT) system participates in ZNP‐induced lysosome–autophagy system changes, especially in the fusion between autophagosomes and lysosomes. MT acetylation is helpful for protecting from ZNP‐induced MT disruption, and it promotes the autophagic degradation process. In conclusion, this study provides valuable information on NM‐induced lysosome–autophagy system changes, particularly with respect to the role of lysophagy and the MT system, which point to some attractive targets for the design of engineered nanoparticles.     

Uncovering the Rab5‐Independent Autophagic Trafficking of Influenza A Virus by Quantum‐Dot‐Based Single‐Virus Tracking

Autophagy is closely related to virus‐induced disease and a comprehensive understanding of the autophagy‐associated infection process of virus will be significant for developing more effective antiviral strategies. However, many critical issues and the underlying mechanism of autophagy in virus entry still need further investigation. Here, this study unveils the involvement of autophagy in influenza A virus entry. The quantum‐dot‐based single‐virus tracking technique assists in real‐time, prolonged, and multicolor visualization of the transport process of individual viruses and provides unambiguous dissection of the autophagic trafficking of viruses. These results reveal that roughly one‐fifth of viruses are ferried into cells for infection by autophagic machineries, while the remaining are not. A comprehensive overview of the endocytic‐ and autophagic‐trafficking process indicates two distinct trafficking pathway of viruses, either dependent on Rab5‐positive endosomes or autophagosomes, with striking similarities. Expressing dominant‐negative mutant of Rab5 suggests that the autophagic trafficking of viruses is independent on Rab5. The present study provides dynamic, precise, and mechanistic insights into the involvement of autophagy in virus entry, which contributes to a better understanding of the relationship between autophagy and virus entry. The quantum‐dot‐based single‐virus tracking is proven to hold promise for autophagy‐related fundamental research.     

A Sequential Target‐Responsive Nanocarrier with Enhanced Tumor Penetration and Neighboring Effect In Vivo

Nanodrug‐based cancer therapy is impeded by poor penetration into deep tumor tissues mainly due to the overexpression of hyaluronic acid (HA) in the tumor extracellular matrix (ECM). Although modification of nanoparticles (NPs) with hyaluronidase (HAase) is a potent strategy, it remains challenging to get a uniform distribution of drug at the tumor site because of the internalization of NPs by the cells in the tumor and HA regeneration. Herein, an intelligent nanocarrier, which can release HAase in response to the acidic tumor microenvironment (pH 6.5) and perform a strong neighboring effect with size reduction to overcome the above two problems and accomplish drug deep tumor penetration in vivo, is reported. In this design, HAase is encapsulated on the surfaces of doxorubicin (DOX) preloaded ZnO‐DOX NPs using a charge convertible polymer PEG‐PAH‐DMMA (ZDHD). The polymer can release HAase to degrade HA in the tumor ECM (pH 6.5). ZnO‐DOX NPs can release DOX in lysosomes (pH 4.5) to induce cell apoptosis, and exert a neighboring effect with size reduction to infect neighboring cells. The hierarchical targeted release of HAase and drugs is demonstrated to enhance tumor penetration and decrease side effects in vivo. This work shows promise for further application of ZDHD NPs in cancer therapy.     

TPGS‐Functionalized Polydopamine‐Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance

A nanocarrier system of d ‐a‐tocopheryl polyethylene glycol 1000 succinate (TPGS)‐functionalized polydopamine‐coated mesoporous silica nanoparticles (NPs) is developed for sustainable and pH‐responsive delivery of doxorubicin (DOX) as a model drug for the treatment of drug‐resistant nonsmall cell lung cancer. Such nanoparticles are of desired particle size, drug loading, and drug release profile. The surface morphology, surface charge, and surface chemical properties are also successfully characterized by a series of techniques such as transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), Brunauer‐Emmett‐Teller (BET) method, thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FTIR). The normal A549 cells and drug‐resistant A549 cells are employed to access the cytotoxicity and cellular uptake of the NPs. The therapeutic effects of TPGS‐conjugated nanoparticles are evaluated in vitro and in vivo. Compared with free DOX and DOX‐loaded NPs without TPGS ligand modification, MSNs‐DOX@PDA‐TPGS exhibits outstanding capacity to overcome multidrug resistance and shows better in vivo therapeutic efficacy. This splendid drug delivery platform can also be sued to deliver other hydrophilic and hydrophobic drugs.     

Methotrexate-conjugated L-lysine coated iron oxide magnetic nanoparticles for inhibition of MCF-7 breast cancer cells

Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase enzyme, is a chemotherapeutic agent for treating a diversity of neoplasms. In this study, we design and developed a new formulation of MTX that serves as drug carrier and examined its cytotoxic effect in vitro. This target drug delivery system is dependent on the release of the MTX within the lysosomal compartment. The iron oxide magnetic nanoparticles (IONPs) were first surface-coated with L-lysine and subsequently conjugated with MTX through amidation between the carboxylic acid end groups on MTX and the amine groups on the IONPs surface. MTX-conjugated L-lysine coated IONPs (F-Lys-MTX NPs) was characterized by X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy, vibrating sample magnetometer, and transmission electron microscopy techniques. The cytotoxicity of the void of MTX and F-Lys-MTX NPs were compared to each other by MTT assay of the treated MCF-7 cell lines. The results showed that the ζ-potential of F-Lys-MTX NPs was about ?5.49?mV and the average size was 43.72?±?4.73?nm. Model studies exhibited the release of MTX via peptide bond cleavage in the presence of proteinase K and at low pH. These studies specify that F-Lys-MTX NPs have a very remarkable anticancer effect, for breast cancer cell lines.     

An Ultra pH‐Sensitive and Aptamer‐Equipped Nanoscale Drug‐Delivery System for Selective Killing of Tumor Cells

Nanotechnology has often been applied in the development of targeted drug‐delivery systems for the treatment of cancer. An ideal nanoscale system for drug delivery should be able to selectively deliver and rapidly release the carried therapeutic drug(s) in cancer cells and, more importantly, not react to off‐target cells so as to eliminate unwanted toxicity on normal tissues. To reach this goal, a selective chemotherapeutic is formulated using a hollow gold nanosphere (HAuNS) equipped with a biomarker‐specific aptamer (Apt), and loaded with the chemotherapy drug doxorubicin (DOX). The formed Apt‐HAuNS‐Dox, approximately 42 nm in diameter, specifically binds to lymphoma tumor cells and does not react to control cells that do not express the biomarker. Through aptamer‐mediated selective cell binding, the Apt‐HAuNS‐Dox is internalized exclusively into the targeted tumor cells, and then released the DOX intracellularly. Of note, although the formed Apt‐HAuNS‐Dox is stable under normal biological conditions (pH 7.4), it appears ultrasensitive to pH change and rapidly releases 80% of the loaded DOX within 2 h at pH 5.0, a condition seen in cell lysosomes. Functional assays using cell mixtures show that the Apt‐HAuNS‐Dox selectively kills lymphoma tumor cells, but has no effect on the growth of the off‐target cells in the same cultures, indicating that this ultra pH‐sensitive Apt‐HAuNS‐Dox can selectively treat cancer through specific aptamer guidance, and will have minimal side effects on normal tissue.     

Surface Functionality of Nanoparticles Determines Cellular Uptake Mechanisms in Mammalian Cells

Nanoparticles (NPs) are versatile scaffolds for numerous biomedical applications including drug delivery and bioimaging. The surface functionality of NPs essentially dictates intracellular NP uptake and controls their therapeutic action. Using several pharmacological inhibitors, it is demonstrated that the cellular uptake mechanisms of cationic gold NPs in both cancer (HeLa) and normal cells (MCF10A) strongly depend on the NP surface monolayer, and mostly involve caveolae and dynamin‐dependent pathways as well as specific cell surface receptors (scavenger receptors). Moreover, these NPs show different uptake mechanisms in cancer and normal cells, providing an opportunity to develop NPs with improved selectivity for delivery applications.     

Reversibly Extracellular pH Controlled Cellular Uptake and Photothermal Therapy by PEGylated Mixed‐Charge Gold Nanostars

Shielding nanoparticles from nonspecific interactions with normal cells/tissues before they reach and after they leave tumors is crucial for the selective delivery of NPs into tumor cells. By utilizing the reversible protonation of weak electrolytic groups to pH changes, long‐chain amine/carboxyl‐terminated polyethylene glycol (PEG) decorated gold nanostars (GNSs) are designed, exhibiting reversible, significant, and sensitive response in cell affinity and therapeutic efficacy to the extracellular pH (pHe) gradient between normal tissues and tumors. This smart nanosystem shows good dispersity and unimpaired photothermal efficacy in complex bioenvironment at pH 6.4 and 7.4 even when their surface charge is neutral. One PEGylated mixed‐charge GNSs with certain surface composition, GNS‐N/C 4 , exhibits high cell affinity and therapeutic efficacy at pH 6.4, and low affinity and almost “zero” damage to cells at pH 7.4. Remarkably, this significant and sensitive response in cell affinity and therapeutic efficacy is reversible as local pH alternated. In vivo, GNS‐N/C 4 shows higher accumulation in tumors and improved photothermal therapeutic efficacy than pH‐insensitive GNSs. This newly developed smart nanosystem, whose cell affinity reversibly transforms in response to pHe gradient with unimpaired biostability, provides a novel effective means of tumor‐selective therapy.     

Insulin-coated gold nanoparticles: a plasmonic device for studying metal-protein interactions

Insulin-capped gold nanoparticles (Au@insulin NPs) are highly sensitive towards pH and heavy metals, due to the protein coating. Au@insulin NPs aggregate and disaggregate reversibly with pH and in the presence of various heavy metal ions, which can be monitored through reversible changes in their optical properties. The sensitivity of the NPs towards different metal ions is dissimilar and depends on the coordinative properties of each specific metal ion, its valence number, concentration, and reaction time (kinetics), representing a simple tool for studying fundamental metal-protein interactions. Moreover, Au@insulin NPs are biocompatible and highly stable at high ionic strengths, due to their robust protein coating.     

Engineering Biomimetic Platesomes for pH‐Responsive Drug Delivery and Enhanced Antitumor Activity

Biomimetic camouflage, i.e., using natural cell membranes for drug delivery, has demonstrated advantages over synthetic materials in both pharmacokinetics and biocompatibility, and so represents a promising solution for the development of safe nanomedicine. However, only limited efforts have been dedicated to engineering such camouflage to endow it with optimized or additional properties, in particular properties critical to a “smart” drug delivery system, such as stimuli‐responsive drug release. A pH‐responsive biomimetic “platesome” for specific drug delivery to tumors and tumor‐triggered drug release is described. This platesome nanovehicle is constructed by merging platelet membranes with functionalized synthetic liposomes and exhibits enhanced tumor affinity, due to its platelet membrane–based camouflage, and selectively releases its cargo in response to the acidic microenvironment of lysosomal compartments. In mouse cancer models, it shows significantly better antitumor efficacy than nanoformulations based on a platesome without pH responsiveness or those based on traditional pH‐sensitive liposomes. A convenient way to incorporate stimuli‐responsive features into biomimetic nanoparticles is described, demonstrating the potential of engineered cell membranes as biomimetic camouflages for a new generation of biocompatible and efficient nanocarriers.     

Drug release behaviors of a pH/temperature sensitive core-shelled bead with alginate and poly(N-acryloyl glycinates)

In this study, a pH/temperature sensitive bead with core-shelled structure, as a drug carrier, was prepared by grafting of N-acryloylglycinates on the surface of sodium alginate beads. The pH and temperature sensitivity of the beads originate from sodium alginate (SA) and copoly(N-acryloylglycinates), respectively. Here, indomethacin (IMC) was selected as a drug model molecule and loaded in SA beads. The release of IMC was systematically investigated as a function of temperature, pH, and SA concentration. The amount of IMC released from beads was as high as 61.6%in pH = 7.4 phosphate buffer solution (PBS) over 620 min, whereas only 27.9% IMC diffused into the pH = 2.1 PBS. In addition, the release rates of IMC at 37.5°C were faster than that at 20.0°C and decreased with increasing SA concentration in the beads. The result indicates that the sensitive beads have the potential to be used as an effective pH/temperature-controlled delivery system in the biomedical fields.     

Protein functionalized tramadol-loaded PLGA nanoparticles: preparation,optimization, stability and pharmacodynamic studies

Poly (d,l-lactide-co-glycolide acid) (PLGA) Nanoparticles (NPs) with sustained drug release and enhanced circulation time presents widely explored non-invasive approach for drug delivery to brain. However, blood-brain barrier (BBB) limits the drug delivery to brain. This can be overcome by anchoring endogenous ligand like Transferrin (Tf) and Lactoferrin (Lf) on the surface of NPs, allowing efficient brain delivery via receptor-mediated endocytosis. The aim of the present investigation was preparation, optimization, characterization and comparative evaluation of targeting efficiency of Tf- vs. Lf-conjugated NPs. Tramadol-loaded PLGA NPs were prepared by nanoprecipitation techniques and optimized using 3³ factorial design. The effect of polymer concentration, stabilizer concentration and organic:aqueous phase ratio were evaluated on particle size (PS) and entrapment efficiency (EE). The formulation was optimized based on desirability for lower PS (<150 nm) and higher EE (>70%). Optimized PLGA NPs were conjugated with Tf and Lf, characterized and evaluated for stability study. Pharmacodynamic study was performed in rat after intravenous administration. The optimized formulation had 100 mg of PLGA, 1% polyvinyl alcohol (PVA) and 1:2 acetone:water ratio. The Lf and Tf conjugation to PLGA NPs was estimated to 186 Tf and 185 Lf molecules per NPs. Lyophilization was optimized at 1:2 ratio of NPs:trehalose. The NPs were found stable for 6 months at refrigerated condition. Pharmacodynamic study demonstrated enhanced efficacy of ligand-conjugated NPs against unconjugated NPs. Conjugated NPs demonstrated significantly higher pharmacological effect over a period of 24 h. Furthermore Lf functionalized NPs exhibited better antinociceptive effect as compared to Tf functionalized NPs.     

Hollow manganese phosphate nanoparticles as smart multifunctional probes for cancer cell targeted magnetic resonance imaging and drug delivery

Multifunctional probes for simultaneous magnetic resonance imaging (MRI) and drug delivery have attracted considerable interest due to their promising potential applications in the early-stage diagnosis and therapy of the diseases. In this study, hollow manganese phosphate nanoparticles (HMP NPs) with an average diameter of 18 nm were synthesized and aminated through silanization, which enabled the covalent conjugation of biocompatible poly(ethylene glycol) (PEG) on their surfaces. The anti-tumor drug doxorubicin (DOX) could be loaded into the hollow cavities. Under physiological conditions (pH 7.4), the NPs showed low MRI T ₁ contrast (r ₁ = 1.19 L·mmol^?1·s^?1), whereas high T ₁ enhancement (r ₁ = 5.22 L·mmol^?1·s^?1) was achieved after dissolving them in endosome/lysosome mimetic conditions (pH 5.4). This is due to the fact that the NPs were easily eroded, which resulted in the release of Mn²⁺ at low pH. To use this interesting phenomenon for targeted DOX drug delivery, we conjugated the tumor-targeting ligand folic acid (FA) on HMP NPs and investigated their drug delivery capacity and cytotoxicity to cell lines expressing different amount of folate receptor (FR). KB cells showed more significant cellular uptake than HeLa cells and A549 cells, as confirmed by confocal laser scanning microscopy (CLSM), flow cytometry and cellular T ₁-weighted MRI. Furthermore, the drug-loaded HMP NPs exhibited greater cytotoxicity to KB cells. Our results suggest that functionalized HMP NPs can act as an effective multifunctional probe for selective diagnosis with MRI, as well as giving efficient targeted drug delivery.      

Drug release behaviors of a pH/temperature sensitive core-shelled bead with alginate and poly(<Emphasis Type="Italic">N</Emphasis>-acryloyl glycinates)

In this study, a pH/temperature sensitive bead with core-shelled structure, as a drug carrier, was prepared by grafting of N-acryloylglycinates on the surface of sodium alginate beads. The pH and temperature sensitivity of the beads originate from sodium alginate (SA) and copoly(N-acryloylglycinates), respectively. Here, indomethacin (IMC) was selected as a drug model molecule and loaded in SA beads. The release of IMC was systematically investigated as a function of temperature, pH, and SA concentration. The amount of IMC released from beads was as high as 61.6%in pH = 7.4 phosphate buffer solution (PBS) over 620 min, whereas only 27.9% IMC diffused into the pH = 2.1 PBS. In addition, the release rates of IMC at 37.5°C were faster than that at 20.0°C and decreased with increasing SA concentration in the beads. The result indicates that the sensitive beads have the potential to be used as an effective pH/temperature-controlled delivery system in the biomedical fields.     

Efficient delivery of antitumor drug to the nuclei of tumor cells by amphiphilic biodegradable poly(L-aspartic acid-co-lactic acid)/DPPE co-polymer nanoparticles

The use of biodegradable polymeric nanoparticles (NPs) for controlled drug delivery has shown significant therapeutic potential. Polyaspartic acid and polylactic acid are the most intensively studied biodegradable polymers. In the present study, novel amphiphilic biodegradable co-polymer NPs, poly(L-aspartic acid-co-lactic acid) with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (poly(AA-co-LA)/DPPE) is synthesized and subsequently used to encapsulate an antitumor drug doxorubicin (DOX). The formulation parameters of the NPs are optimized to improve encapsulation efficiency. The resulting drug-loaded NPs possess better size homogeneity (polydispersity) and exhibit pH-responsive drug release profiles. Cellular viability assays indicate that the poly(AA-co-LA)/DPPE NPs did not induce cell death, whereas doxorubicin encapsulated NPs were cytotoxic to various types of tumor cells. In addition, the free NPs could not enter the cell nuclei after internalized in tumor cells. The DOX-loaded NPs exhibit efficient intracellular delivery in tumor cells with co-localization in lysosome and delay entering into the nucleus, which suggests a time- and pH-dependent drug release profile within cells. When applied to deliver chemotherapeutics to a mouse xenograft model of human lung adenocarcinoma, DOX-loaded NPs have a comparable antitumor activity with free DOX, and greatly reduce systemic toxicity and mortality. The delivery of cytotoxic drugs directly to the nucleus specifically within tumor cells is of great interest. These results demonstrate the feasibility of the application of the amphiphilic polyaspartic acid derivative, poly(AA-co-LA)/DPPE, as a nanocarrier for cell nuclear delivery of potent antitumor drugs.