Exposure to environmental airborne particulate matter caused wide-ranged transcriptional changes and accelerated Alzheimer's-related pathology: A mouse study.

Air pollution poses a significant threat to human health, though a clear understanding of its mechanism remains elusive. In this study, we sought to better understand the effects of various sized particulate matter from polluted air on Alzheimer's disease (AD) development using an AD mouse model. We exposed transgenic Alzheimer's mice in their prodromic stage to different sized particulate matter (PM), with filtered clean air as control. After 3 or 6 months of exposure, mouse brains were harvested and analyzed. RNA-seq analysis showed that various PM have differential effects on the brain transcriptome, and these effects seemed to correlate with PM size. Many genes and pathways were affected after PM exposure. Among them, we found a strong activation in mRNA Nonsense Mediated Decay pathway, an inhibition in pathways related to transcription, neurogenesis and survival signaling as well as angiogenesis, and a dramatic downregulation of collagens. Although we did not detect any extracellular Aß plaques, immunostaining revealed that both intracellular Aß1-42 and phospho-Tau levels were increased in various PM exposure conditions compared to the clean air control. NanoString GeoMx analysis demonstrated a remarkable activation of immune responses in the PM exposed mouse brain. Surprisingly, our data also indicated a strong activation of various tumor suppressors including RB1, CDKN1A/p21 and CDKN2A/p16. Collectively, our data demonstrated that exposure to airborne PM caused a profound transcriptional dysregulation and accelerated Alzheimer's-related pathology.

ß-Amyloid targeting nanodrug for neuron-specific delivery of nucleic acids in Alzheimer's disease mouse models.

Delivery of therapeutic substances into the brain poses a significant challenge in the treatment of neurological disorders. This is primarily due to the blood-brain barrier (BBB), which restricts access, alongside the limited stability and distribution of these agents within the brain tissue. Here we demonstrate an efficient delivery of microRNA (miRNA) and antisense RNA preferentially to neurons compared to astroglia in the brain of healthy and Alzheimer's disease mice, via disulfide-linked conjugation with poly(ß-L-malic acid-trileucine)-copolymer a biodegradable, amphiphilic, and multivalent platform. By conjugating a D-configured (D3)-peptide (vector) for specific targeting, highly efficient delivery across the BBB is achieved through the Low-Density Lipoprotein Receptor-Related Protein-1 (LRP-1) transcytosis pathway, amyloid beta (Aß) peptides. Nanodrug distribution was determined by fluorescent labeling and analyzed by microscopy in neurons, astroglia, and in extracellular amyloid plaques typical for Alzheimer's disease. Whereas D-configured BBB-vectors can efficiently target neurons, L-configured (e.g., AP2-peptide) guided vector can only cross BBB but not seem to bind neurons. An analysis of post-injection fluorescence distribution, and RNA-seq followed by real-time PCR validation, confirmed a successful in vivo delivery of morpholino-miRNA-186 nanoconjugates into mouse brain. The size and fluorescence intensity of the intracellular nanodrug particulates were analyzed and verified by a competition with non-fluorescent conjugates. Differentially expressed genes (DEGs) from RNA-seq were identified in the nanodrug injected mice, and the changes of selected DEGs related to Alzheimer's disease were further validated by western blot and real-time PCR. Collectively, these results demonstrated that D3-peptide-conjugated nanopolymer drug is able to achieve neuron-selective delivery of miRNA and can serve as an efficient brain delivery vehicle in Alzheimer's disease (AD) mouse models.

Signature Effects of Vector-Guided Systemic Nano Bioconjugate Delivery Across Blood-Brain Barrier of Normal, Alzheimer's, and Tumor Mouse Models.

The ability to cross the blood-brain barrier (BBB) is critical for targeted therapy of the central nerve system (CNS). Six peptide vectors were covalently attached to a 50 kDa poly(ß-l-malic acid)-trileucine polymer forming P/LLL(40%)/vector conjugates. The vectors were Angiopep-2 (AP2), B6, Miniap-4 (M4), and d-configurated peptides D1, D3, and ACI-89, with specificity for transcytosis receptors low-density lipoprotein receptor-related protein-1 (LRP-1), transferrin receptor (TfR), bee venom-derived ion channel, and Aß/LRP-1 related transcytosis complex, respectively. The BBB-permeation efficacies were substantially increased ("boosted") in vector conjugates of P/LLL(40%). We have found that the copolymer group binds at the endothelial membrane and, by an allosterically membrane rearrangement, exposes the sites for vector-receptor complex formation. The specificity of vectors is indicated by competition experiments with nonconjugated vectors. P/LLL(40%) does not function as an inhibitor, suggesting that the copolymer binding site is eliminated after binding of the vector-nanoconjugate. The two-step mechanism, binding to endothelial membrane and allosteric exposure of transcytosis receptors, is supposed to be an integral feature of nanoconjugate-transcytosis pathways. In vivo brain delivery signatures of the nanoconjugates were recapitulated in mouse brains of normal, tumor (glioblastoma), and Alzheimer's disease (AD) models. BBB permeation of the tumor was most efficient, followed by normal and then AD-like brain. In tumor-bearing and normal brains, AP2 was the top performing vector; however, in AD models, D3 and D1 peptides were superior ones. The TfR vector B6 was equally efficient in normal and AD-model brains. Cross-permeation efficacies are manifested through modulated vector coligation and dosage escalation such as supra-linear dose dependence and crossover transcytosis activities.

Multifunctional Nanopolymers for Blood-Brain Barrier Delivery and Inhibition of Glioblastoma Growth through EGFR/EGFRvIII, c-Myc, and PD-1.

Glioblastoma (GBM) is the most prevalent primary brain cancer in the pediatric and adult population. It is known as an untreatable tumor in urgent need of new therapeutic approaches. The objective of this work was to develop multifunctional nanomedicines to treat GBM in clinical practice using combination therapy for several targets. We developed multifunctional nanopolymers (MNPs) based on a naturally derived biopolymer, poly(ß-L-malic) acid, which are suitable for central nervous system (CNS) treatment. These MNPs contain several anticancer functional moieties with the capacity of crossing the blood-brain barrier (BBB), targeting GBM cells and suppressing two important molecular markers, tyrosine kinase transmembrane receptors EGFR/EGFRvIII and c-Myc nuclear transcription factor. The reproducible syntheses of MNPs where monoclonal antibodies are replaced with AP-2 peptide for effective BBB delivery were presented. The active anticancer inhibitors of mRNA/protein syntheses were Morpholino antisense oligonucleotides (AONs). Two ways of covalent AON-polymer attachments with and without disulfide bonds were explored. These MNPs bearing AONs to EGFR/EGFRvIII and c-Myc, as well as in a combination with the polymer-attached checkpoint inhibitor anti-PD-1 antibody, orchestrated a multi-pronged attack on intracranial mouse GBM to successfully block tumor growth and significantly increase survival of brain tumor-bearing animals.

Small-Sized Co-Polymers for Targeted Delivery of Multiple Imaging and Therapeutic Agents.

Research has increasingly focused on the delivery of high, often excessive amounts of drugs, neglecting negative aspects of the carrier's physical preconditions and biocompatibility. Among them, little attention has been paid to "small but beautiful" design of vehicle and multiple cargo to achieve effortless targeted delivery into deep tissue. The design of small biopolymers for deep tissue targeted delivery of multiple imaging agents and therapeutics (mini-nano carriers) emphasizes linear flexible polymer platforms with a hydrodynamic diameter of 4 nm to 10 nm, geometrically favoring dynamic juxtaposition of ligands to host receptors, and economic drug content. Platforms of biodegradable, non-toxic poly(ß-l-malic acid) of this size carrying multiple chemically bound, optionally nature-derived or synthetic affinity peptides and drugs for a variety of purposes are described in this review with specific examples. The size, shape, and multiple attachments to membrane sites accelerate vascular escape and fast blood clearance, as well as the increase in medical treatment and contrasts for tissue imaging. High affinity antibodies routinely considered for targeting, such as the brain through the blood-brain barrier (BBB), are replaced by moderate affinity binding peptides (vectors), which penetrate at high influxes not achievable by antibodies.

Author Correction: Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20129-9.

Single- and Multi-Arm Gadolinium MRI Contrast Agents for Targeted Imaging of Glioblastoma.

BACKGROUND: Position of gadolinium atom(s) plays a key role in contrast enhancement of gadolinium-based contrast agents. To gain a better understanding of effects of distance of gadolinium in relation to the nanoconjugate platform, we designed and synthesized single- and multi-arm ("star") gadolinium conjugates equipped with antibody and peptides for targeting. The contrast agents were studied for their tumor imaging performance in a glioma mouse model. MATERIALS AND METHODS: Antibody- and peptide-targeted nano contrast agents (NCAs) were synthesized using polymalic acid platforms of different sizes. Gadolinium-DOTA and intermediates were attached as amides and targeting agents such as antibodies and peptides as thioethers. For in vivo experiments, we used human U87MG xenografts as glioma models. Magnetic resonance imaging (MRI) was performed on a Bruker BioSpec 94/20USR 9.4 T small-animal scanner. Delivery of contrast agents across the blood-brain barrier was studied by fluorescent microscopy. RESULTS: All contrast agents accumulated into tumor and showed composition-dependent imaging performance. Peptide-targeted mini-NCAs had hydrodynamic diameters in the range 5.2-9.4 nm and antibody-targeted NCAs had diameters in the range 15.8-20.5 nm. Zeta potentials were in the range of -5.4--8.2 mV and -4.6--8.8 mV, respectively. NCAs showed superior relaxivities compared to MultiHance at 9.4 T. The signal enhancement indicated maximum accumulation in tumor 30-60 minutes after intravenous injection of the mouse tail vein. Only targeted NCAs were retained in tumor for up to 3 hours and displayed contrast enhancement. CONCLUSION: The novel targeted NCAs with star-PEG features displayed improved relaxivity and greater contrast compared with commercial MultiHance contrast agent. The enhancement by mini-NCAs showed clearance of tumor contrast after 3 hours providing a suitable time window for tumor diagnosis in clinics. The technology provides a great tool with the promise of differential MRI diagnosis of brain tumors.

Author Correction: Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Magnetic iron oxide nanoparticles for imaging, targeting and treatment of primary and metastatic tumors of the brain.

Magnetic nanoparticles in general, and iron oxide nanoparticles in particular, have been studied extensively during the past 20 years for numerous biomedical applications. The main applications of these nanoparticles are in magnetic resonance imaging (MRI), magnetic targeting, gene and drug delivery, magnetic hyperthermia for tumor treatment, and manipulation of the immune system by macrophage polarization for cancer treatment. Recently, considerable attention has been paid to magnetic particle imaging (MPI) because of its better sensitivity compared to MRI. In recent years, MRI and MPI have been combined as a dual or multimodal imaging method to enhance the signal in the brain for the early detection and treatment of brain pathologies. Because magnetic and iron oxide nanoparticles are so diverse and can be used in multiple applications such as imaging or therapy, they have attractive features for brain delivery. However, the greatest limitations for the use of MRI/MPI for imaging and treatment are in brain delivery, with one of these limitations being the brain-blood barrier (BBB). This review addresses the current status, chemical compositions, advantages and disadvantages, toxicity and most importantly the future directions for the delivery of iron oxide based substances across the blood-brain barrier for targeting, imaging and therapy of primary and metastatic tumors of the brain.

Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy.

Brain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood-brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(ß-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.

A Combination of Tri-Leucine and Angiopep-2 Drives a Polyanionic Polymalic Acid Nanodrug Platform Across the Blood-Brain Barrier.

One of the major problems facing the treatment of neurological disorders is the poor delivery of therapeutic agents into the brain. Our goal is to develop a multifunctional and biodegradable nanodrug delivery system that crosses the blood-brain barrier (BBB) to access brain tissues affected by neurological disease. In this study, we synthesized a biodegradable nontoxic ß-poly(l-malic acid) (PMLA or P) as a scaffold to chemically bind the BBB crossing peptides Angiopep-2 (AP2), MiniAp-4 (M4), and the transferrin receptor ligands cTfRL and B6. In addition, a trileucine endosome escape unit (LLL) and a fluorescent marker (rhodamine or rh) were attached to the PMLA backbone. The pharmacokinetics, BBB penetration, and biodistribution of nanoconjugates were studied in different brain regions and at multiple time points via optical imaging. The optimal nanoconjugate, P/LLL/AP2/rh, produced significant fluorescence in the parenchyma of cortical layers II/III, the midbrain colliculi, and the hippocampal CA1-3 cellular layers 30 min after a single intravenous injection; clearance was observed after 4 h. The nanoconjugate variant P/LLL/rh lacking AP2, or the variant P/AP2/rh lacking LLL, showed significantly less BBB penetration. The LLL moiety appeared to stabilize the nanoconjugate, while AP2 enhanced BBB penetration. Finally, nanoconjugates containing the peptides M4, cTfRL, and B6 displayed comparably little and/or inconsistent infiltration of brain parenchyma, likely due to reduced trans-BBB movement. P/LLL/AP2/rh can now be functionalized with intra-brain targeting and drug treatment moieties that are aimed at molecular pathways implicated in neurological disorders.

Covalent nano delivery systems for selective imaging and treatment of brain tumors.

Nanomedicine is a rapidly evolving form of therapy that holds a great promise for superior drug delivery efficiency and therapeutic efficacy than conventional cancer treatment. In this review, we attempt to cover the benefits and the limitations of current nanomedicines with special attention to covalent nano conjugates for imaging and drug delivery in the brain. The improvement in brain tumor treatment remains dismal despite decades of efforts in drug development and patient care. One of the major obstacles in brain cancer treatment is the poor drug delivery efficiency owing to the unique blood-brain barrier (BBB) in the CNS. Although various anti-cancer agents are available to treat tumors outside of the CNS, the majority fails to cross the BBB. In this regard, nanomedicines have increasingly drawn attention due to their multi-functionality and versatility. Nano drugs can penetrate BBB and other biological barriers, and selectively accumulate in tumor cells, while concurrently decreasing systemic toxicity.

Mimicking Neuroligin-2 Functions in ß-Cells by Functionalized Nanoparticles as a Novel Approach for Antidiabetic Therapy.

Both pancreatic ß-cell membranes and presynaptic active zones of neurons include in their structures similar protein complexes, which are responsible for mediating the secretion of bioactive molecules. In addition, these membrane-anchored proteins regulate interactions between neurons and guide the formation and maturation of synapses. These proteins include the neuroligins (e.g., NL-2) and their binding partners, the neurexins. The insulin secretion and maturation of ß-cells is known to depend on their 3-dimensional (3D) arrangement. It was also reported that both insulin secretion and the proliferation rates of ß-cells increase when cells are cocultured with clusters of NL-2. Use of full-length NL-2 or even its exocellular domain as potential ß-cell functional enhancers is limited by the biostability and bioavailability issues common to all protein-based therapeutics. Thus, based on molecular modeling approaches, a short peptide with the potential ability to bind neurexins was derived from the NL-2 sequence. Here, we show that the NL-2-derived peptide conjugates onto innovative functional maghemite (γ-Fe2O3)-based nanoscale composite particles enhance ß-cell functions in terms of glucose-stimulated insulin secretion and protect them under stress conditions. Recruiting the ß-cells' "neuron-like" secretory machinery as a target for diabetes treatment use has never been reported before. Such nanoscale composites might therefore provide a unique starting point for designing a novel class of antidiabetic therapeutic agents that possess a unique mechanism of action.

Efficient penetration of ceric ammonium nitrate oxidant-stabilized gamma-maghemite nanoparticles through the oval and round windows into the rat inner ear as demonstrated by MRI.

We aimed to evaluate the magnetic resonance imaging (MRI) contrast effect and delivery efficiency through the middle ear into the inner ear using novel super-paramagnetic maghemite (γ-Fe2 O3 ) nanoparticles (NPs) generated using ceric ammonium nitrate (CAN)-mediated oxidation of Fe3 O4 NPs (CAN-γ-Fe2 O3 NPs). The CAN-γ-Fe2O3 NPs, having hydrodynamic diameters of 50-60 nm and potentials of +55.2 mV, displayed super-paramagnetic behavior characterized by a saturation magnetization Ms of 75.2 emu/g NPs. The r1 and r2* relaxivity (curve slopes) values were 0.0015 and 189 mmol-1  s-1 , respectively, indicating strong T2* relaxation maghemite-based NPs. The CAN-γ-Fe2 O3 NPs were stable in the 7.0 T magnetic field. At 3 h after the tympanic medial wall administration, the NPs had significantly located to the cochlea and vestibule. The signal started to recover at 6 h in the ipsilateral cochlea and by 2 d in the vestibule post-administration. There was no difference in the signal intensity between the left and right ears on the 14th d. Prussian blue staining for iron demonstrated NP distribution in the inner ear tissue. The novel CAN-γ-Fe2 O3 NPs are a strong MRI T2 contrast agent and penetrated the round and oval windows and have potential application in the molecular imaging of the inner ear. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1883-1891, 2017.

Maghemite-human serum albumin hybrid nanoparticles: towards a theranostic system with high MRI r2* relaxivity.

Human Serum Albumin (HSA) is the most abundant plasma protein in human blood, and therefore, it is the material of choice for the development of particulate formulations due to its biodegradable and biocompatible nature. Over the last decade, HSA nanoparticles (NPs) have been prepared mostly using desolvation techniques and evaluated as promising drug carriers. In addition, controlling the particle size has become a primary concern while formulating such nanoparticulate systems. Since many of these HSA-based carrier systems have often demonstrated batch-to-batch fabrication variability, significant efforts have been made to develop and characterize HSA-based NPs featuring a robust and controllable particle size, by using a desolvation/cross-linking-type Divinyl Sulfone (DVS)-mediated nanofabrication method. For this purpose and for global multi-parameter fabrication process optimization, a statistically significant Design of Experiment (DoE, MINITAB® 17 DoE software) methodology has been successfully implemented. It aimed to disclose an optimal set of HSA NP fabrication conditions in order to afford highly reproducible and stable 23.05 ± 5.3 nm-sized DoE-globally optimized core HSA NPs. Due to the use of bifunctional DVS as a cross-linker for the preparation of such DoE-optimized HSA NPs, their surface contains a variety of free functional groups which are available for further second step functional modifications. Moreover, related hybrid organic/inorganic nanosystems consisting of DoE-optimized HSA NPs that encapsulated hydrophilic (NH4)2Ce(IV)(NO3)6 (Ceric Ammonium Nitrate - CAN) modified γ-Fe2O3 NPs (CAN-maghemite or CAN-γ-Fe2O3 NPs), which enable medical imaging using magnetic resonance imaging (MRI), have also been fabricated and characterized. The resulting hybrid magnetic NPs are a quite powerful T2* contrast agent (r2* of 482 mM-1 s-1), which may be used as a powerful dual phase platform for both therapeutic (drug delivery) and diagnostic imaging (MRI) applications.

Towards hybrid biocompatible magnetic rHuman serum albumin-based nanoparticles: use of ultra-small (CeLn)3/4+ cation-doped maghemite nanoparticles as functional shell.

Human serum albumin (HSA) is a protein found in human blood. Over the last decade, HSA has been evaluated as a promising drug carrier. However, not being magnetic, HSA cannot be used for biomedical applications such as magnetic resonance imaging (MRI) and magnetic drug targeting. Therefore, subsequent composites building on iron oxide nanoparticles that are already used clinically as MRI contrast agents are extensively studied. Recently and in this context, innovative fully hydrophilic ultra-small CAN-stabilized maghemite ((CeLn)(3/4+)-γ-Fe2O3) nanoparticles have been readily fabricated. The present study discusses the design, fabrication, and characterization of a dual phase hybrid core (rHSA)-shell ((CeLn)(3/4+)-γ-Fe2O3 NPs) nanosystem. Quite importantly and in contrast to widely used encapsulation strategies, rHSA NP surface-attached (CeLn)(3/4+)-γ-Fe2O3 NPs enabled to exploit both rHSA (protein functionalities) and (CeLn)(3/4+)-γ-Fe2O3 NP surface functionalities (COOH and ligand L coordinative exchange) in addition to very effective MRI contrast capability due to optimal accessibility of H2O molecules with the outer magnetic phase. Resulting hybrid nanoparticles might be used as a platform modular system for therapeutic (drug delivery system) and MR diagnostic purposes.

Physico-chemical and toxicological characterization of iron-containing albumin nanoparticles as platforms for medical imaging.

Iron oxide-containing magnetic nanoparticles (MNPs) have certain advantages over currently used contrast agents for tumor imaging by magnetic resonance imaging (MRI) as they offer the possibility of functionalization with ligands and tracers. Functionalized MNPs also may be used for targeted tumor therapy. In the current study nanoparticles (NPs) consisting of recombinant human serum albumin (rHSA) with incorporated hydrophilic (NH4)2Ce(IV)(NO3)6-γ-Fe2O3 particles (CAN maghemite particles) for medical imaging were produced and characterized. For this purpose CAN maghemite particles were incorporated into an rHSA matrix to yield rHSA-NPs. The resulting NPs were analyzed by transmission electron microscopy, photon correlation spectroscopy, and atomic absorption. The sizes of the manufactured NP were 170 ± 10 nm, and the zeta-potential was -50 ± 3 mV. The NPs remained stable when stored after lyophilization with sucrose 3% [w/v] as a cryoprotector. They showed pro-inflammatory properties without cell and animal toxicity in vivo and were highly contrasting in MRI. In conclusion, this report introduces novel rHSA NP with favorable properties containing iron oxide for detection by MRI.

miR-142 orchestrates a network of actin cytoskeleton regulators during megakaryopoiesis.

Genome-encoded microRNAs (miRNAs) provide a posttranscriptional regulatory layer that controls the differentiation and function of various cellular systems, including hematopoietic cells. miR-142 is one of the most prevalently expressed miRNAs within the hematopoietic lineage. To address the in vivo functions of miR-142, we utilized a novel reporter and a loss-of-function mouse allele that we have recently generated. In this study, we show that miR-142 is broadly expressed in the adult hematopoietic system. Our data further reveal that miR-142 is critical for megakaryopoiesis. Genetic ablation of miR-142 caused impaired megakaryocyte maturation, inhibition of polyploidization, abnormal proplatelet formation, and thrombocytopenia. Finally, we characterized a network of miR-142-3p targets which collectively control actin filament homeostasis, thereby ensuring proper execution of actin-dependent proplatelet formation. Our study reveals a pivotal role for miR-142 activity in megakaryocyte maturation and function, and demonstrates a critical contribution of a single miRNA in orchestrating cytoskeletal dynamics and normal hemostasis.DOI: http://dx.doi.org/10.7554/eLife.01964.001.

Ce3/4+ cation-functionalized maghemite nanoparticles towards siRNA-mediated gene silencing.

Pre-formed Massart magnetite (Fe3O4) nanoparticles (NPs) have been successfully modified by positively charged lanthanide Ce(iii/iv) cations/[CeLn]3/4+ complexes by using a strong mono-electronic Ceric Ammonium Nitrate oxidant (CAN) as a Ce donor. The doping process is promoted by high-power ultrasonic irradiation. The reaction has been statistically optimized by Design of Experiments (DoE, MINITAB® 16 DoE software) to afford globally optimized magnetically responsive ultra-small 6.61 ± 2.04 nm-sized CANDOE-γ-Fe2O3 NPs that are highly positively charged (ξ potential: +45.7 mV). This innovative inorganic DoE-optimized NP surface modification by [CeLn]3/4+ complexes enables an effective "fully inorganic-type" coordination attachment of a branched poly-cationic 25 kDa b-PEI25 polymer for siRNA loading and gene silencing. This innovative NP platform technology paves an efficient way for the successful development of a wide range of biomedicine and diagnostic-related applications.