Nanoparticles For Delivery Research Articles

Solid lipid nanoparticles for transdermal delivery of curcumin: Optimization using factorial design and in vitro characterization

This study aimed to design and optimize Curcumin (CUR) loaded solid lipid nanoparticle (SLNs) transdermal formulations by nano emulsion template method. A 3 factor, 2 level Box-Behnken design was used to evaluate the effect of three independent variables viz., Amount of Span 60 (X1), Tween 60 (X2) and Stearyl alcohol (X3) on dependent variables viz., Particle size (Y1), entrapment efficiency (Y2) and zeta potential (Y3). Optimization study signifies that amount of formulation components viz., Span 60, Tween 60 and Stearyl alcohol influence the vesicle size, entrapment efficiency and Zeta potential. The numerical optimization was validated within the design space. The OP-CUR-SLNs exhibited good entrapment efficiency and particle size. Further the OP-CUR-SLNs loaded transdermal carbopol gel shows good in vitro drug release and better ex vivo permeation than the plain CUR loaded gel, which concludes CUR-SLNs considered to be a successful topical transdermal drug delivery system and provide a sustained release of encapsulated drug. Furthermore, CUR-SLNs loaded carbopol gel considered to be non-irritant and safe to be applied on the skin for the intended period of time.

Cystine-Modified Lignin-Copper Coordination Nanocarriers Improve the Therapeutic Efficacy of Tyrosine Kinase Inhibition via Cuproptosis.

The clinical application of tyrosine kinase inhibitors (TKIs) is rapidly growing and has emerged as a cornerstone in the treatment of both solid tumors and hematologic malignancies. However, resistance to TKI targets and disease progression remain inevitable. Nanocarrier-mediated delivery has emerged as a promising strategy to overcome the limitations of the TKI application. We utilized the facile modification of lignin polyhydroxyl groups to synthesize cystine-grafted lignin-copper coordinated nanoparticles for TKI delivery via the Mannich reaction. The materials exhibited a stable, uniform morphology and effectively encapsulated and delivered a variety of TKI inhibitors. Moreover, we optimized the fabrication process and found that the material could release the encapsulated drug in response to both pH and GSH. These nanoparticles significantly enhanced the therapeutic activity of TKIs both in vitro and in vivo through cuproptosis while demonstrating good biosafety. We propose a novel strategy for the targeted delivery of TKI inhibitors by combining cuproptosis with modified lignin. This approach not only offers new strategies for the clinical application of TKIs but also provides novel insights and inspiration for the modified use of lignin.

Development of propranolol loaded SLN for transdermal delivery: in-vitro characterization and skin deposition studies.

The study aimed to formulate solid lipid nanoparticles (SLNs) for the transdermal delivery of PPL to improve skin retention and efficacy. The particle size distribution of SLNs was determined and the morphology of SLNs was also analyzed by SEM. In-vitro, ex-vivo and in vivo evaluations were done for PPL loaded SLN. The safety of drug delivery systems was assayed using MTT test. The results indicated successful encapsulation of PPL in SLNs (59.38%), which exhibited a spherical shape and smooth surface. Compared to PPL solution, SLNs demonstrated a prolonged drug release profile in vitro. Stability tests over three months showed no significant changes in entrapment efficiency or size distribution. Enhanced permeation through shed snake and rat skin was observed with SLNs compared to the PPL solution. Ex-vivo and in vivo studies confirmed that PPL-loaded SLNs significantly increased drug content in the skin. Importantly, the SLNs displayed biocompatibility, as no significant cytotoxic effects were noted, and they were nonirritating to rat skin. To the best of our knowledge, this is the first study that indicates SLNs can be considered as a promising nanocarriers for transdermal delivery of PPL.

CircPRKD3-loaded exosomes concomitantly elicit tumor growth inhibition and glioblastoma microenvironment remodeling via inhibiting STAT3 signaling.

Glioblastoma stem cells (GSCs) and their exosomes (exos) are involved in shaping the immune microenvironment, which is important for tumor invasion and recurrence. However, studies involving GSC-derived exosomal circular RNAs (GDE-circRNAs) in regulating tumor microenvironment (TME) remain unknown. Here, we comprehensively evaluated the significance of a novel immune-related GDE-circRNA in glioma microenvironment. GDE-circPRKD3 was screened out through high-throughput sequencing and verified by RT-PCR, sanger sequencing and RNase R assays. A series of in vitro and in vivo experiments were performed to investigate the function of GDE-circPRKD3. RNA-seq, RNA immunoprecipitation, multicolor flow cytometry and western blotting were used to explore the regulation of GDE-circPRKD3 on STAT3 signaling-mediated TME remodeling. We have characterized a circRNA PRKD3 in GSC exosomes, and lower circPRKD3 expression predicts a worse prognosis for glioblastoma patients. Overexpression of GDE-circPRKD3 significantly impairs the biological competence of glioma and prolongs the survival of xenograft mice. GDE-circPRKD3 binds to HNRNPC in an m6A-dependent manner, accelerates mRNA decay of IL6ST and inhibits downstream target STAT3. Notably, GDE-circPRKD3 promotes CXCL10 secretion by reprogramming tumor-associated macrophages, which in turn recruits CD8+ tumor infiltrating lymphocytes against GBM. Moreover, brain-targeted lipid nanoparticle delivery of circPRKD3 combined with immune checkpoint blockade therapy achieves significant combinatorial benefits. This study provides a novel mechanism by which GDE-circPRKD3 relies on STAT3 signaling to remodel immunosuppressive TME and offers a potential RNA immunotherapy strategy for GBM treatment.

Microenvironment engineering by targeted delivery of Ag nanoparticles for boosting electrocatalytic CO2 reduction reaction

Creating and maintaining a favorable microenvironment for electrocatalytic CO2 reduction reaction (eCO2RR) is challenging due to the vigorous interactions with both gas and electrolyte solution during the electrocatalysis. Herein, to boost the performance of eCO2RR, a unique synthetic method that deploys the in situ reduction of precoated precursors is developed to produce activated Ag nanoparticles (NPs) within the gas diffusion layer (GDL), where the thus-obtained Ag NPs-Skeleton can block direct contact between the active Ag sites and electrolyte. Specifically, compared to the conventional surface loading mode in the acidic media, our freestanding and binder free electrode can achieve obvious higher CO selectivity of 94%, CO production rate of 23.3 mol g−1 h−1, single-pass CO2 conversion of 58.6%, and enhanced long-term stability of 8 hours. Our study shows that delivering catalysts within the GDL does not only gain the desired physical protection from GDL skeleton to achieve a superior local microenvironment for more efficient pH-universal eCO2RR, but also manifests the pore structures to effectively address gas accumulation and flood issues.

Integrating engineered nanomaterials with extracellular vesicles: advancing targeted drug delivery and biomedical applications

Extracellular vesicles (EVs), natural membrane-bound structures released by cells, offer a promising platform for precise and targeted delivery of therapeutic payloads, including drugs and nanoparticles. This comprehensive review explores the integration of engineered nanomaterials with EVs to advance drug delivery systems. It covers various aspects of this integration, including techniques for synthesizing, loading, characterizing, and applying nanomaterials within EVs. Methodologies for integrating diverse nanocarriers like nanoparticles, liposomes, and quantum dots into EVs are discussed, along with characterization methods such as electron microscopy and light scattering. Attention is also given to considerations of biological compatibility, safety assessments, and strategies for surface modification to enhance targeting precision. Highlighting various applications, including targeted drug delivery, cancer therapy, and vaccine development, the review underscores the potential of EV-nanomaterial hybrids to leverage EVs’ innate targeting capabilities and the versatility of nanomaterials. However, it also addresses challenges such as scalability, standardization, and safety that must be overcome to facilitate the clinical translation of these promising biomedical solutions.

Atomized Neutrophil Membrane-coated MOF Nanoparticles for Direct Delivery of Dexamethasone for Severe Pneumonia.

Dexamethasone has proven life-saving in severe acute respiratory syndrome (SARS) and COVID-19 cases. However, its systemic administration is accompanied by serious side effects. Inhalation delivery of dexamethasone (Dex) faces challenges such as low lung deposition, brief residence in the respiratory tract, and the pulmonary mucus barrier, limiting its clinical use. Neutrophil cell membrane-derived nanovesicles, with their ability to specifically target hyper-activated immune cells and excellent mucus permeability, emerge as a promising carrier for pulmonary inhalation therapy. We designed a novel UiO66 metal-organic framework nanoparticle loaded with Dex and coated with neutrophil cell membranes (UiO66-Dex@NMP) for targeted therapy of severe pneumonia. This was achieved by loading Dex into UiO66 pores and subsequently coating with neutrophil membranes for functionalization. Drug release experiments revealed UiO66-Dex@NMP to exhibit favorable sustained-release properties. Additionally, UiO66-Dex@NMP demonstrated excellent targeting capabilities both in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS)-induced pneumonia, UiO66-Dex@NMP significantly reduced lung inflammation compared to both the control model and Dex administered via inhalation. Histopathological analysis further confirmed UiO66-Dex@NMP's ability to alleviate lung tissue damage. UiO66-Dex@NMP represents a novel and safe inhaled delivery carrier for Dex, offering valuable insights into the clinical management of respiratory diseases, including severe pneumonia.

Recent Advances in Monodisperse Gold Nanoparticle Delivery, Synthesis, and Emerging Applications in Cancer Therapy

Recent Advances in Monodisperse Gold Nanoparticle Delivery, Synthesis, and Emerging Applications in Cancer Therapy

Glucose-Responsive Insulin Delivery via Surface-Functionalized Titanium Dioxide Nanoparticles: A Promising Theragnostic against Diabetes Mellitus.

Glucose-dependent insulin delivery systems have been recognized as a promising approach for controlling blood sugar levels in individuals with diabetes mellitus (DM). Recently, titanium dioxide nanoparticles have garnered huge attention in scientific research for their small size and effective drug delivery capabilities. In this study, we developed alizarin (AL)-capped phenylboronic acid (PBA)-functionalized titanium dioxide nanoparticles (TiO2) for glucose-sensitive insulin delivery (TiO2-PBA-INS-AL) aiming to manage both blood sugar levels and its associated organ pathology in DM. The synthesized nanoparticles demonstrated favorable loading capacity as well as high insulin encapsulation efficiency. Initial studies demonstrated glucose-responsive insulin release from TiO2-PBA-INS-AL in a cell-free environment upon exposure to different glucose concentrations. Notably, in vitro experiments revealed that insulin release from TiO2-PBA-INS-AL was more effective in muscle cells (primary glucose storage cells) compared to lung cells when subjected to different glucose concentrations (5.5-25 mM), indicating a glucose-sensitive intracellular insulin delivery mechanism. Furthermore, treatment with TiO2-PBA-INS-AL significantly enhanced GLUT4 translocation and glucose utilization in muscle cells treated with sodium palmitate (PA, 0.75 mM), compared to treatments with TiO2 or insulin alone. In diabetic animal models, a single oral dose of TiO2-PBA-INS-AL maintained normoglycemia for up to 12 h, indicating a significant improvement over subcutaneous or oral insulin treatment. Oral administration of TiO2-PBA-INS-AL also increased insulin bioavailability in both serum and muscle tissue compared to other administration methods. Besides, TiO2-PBA-INS-AL treatment showed no toxicity against both in vitro and in vivo models. Taken together, this nanocarrier-based drug delivery system mimics the natural regulation of insulin secretion in a noninvasive manner, enhancing patient adherence, reducing the risk of hyperglycemia, and improving diabetes management.

Elucidating a Tumor-Selective Nanoparticle Delivery Mechanism at the Colorectal Lumen-Tumor Interface for Precise Local Cancer Therapy.

Although various colorectal cancer (CRC)-targeted nanoparticles have been developed to selectively deliver anticancer agents to tumor tissues, severe off-target side effects still persist due to unwanted systemic nanoparticle distribution, limiting the therapeutic outcome. Here, by elucidating a tumor-selective nanoparticle delivery mechanism occurring at the colorectal lumen-tumor interface, an alternative CRC-targeted delivery route is proposed, which enables highly tumor-selective delivery without systemic distribution, through direct drug delivery from the outside of the body (colorectal lumen) to tumors in the colorectum. Owing to the presence of accessible tumor-specific receptors such as CD44 at the colorectal lumen-tumor interface, but not at the colorectal lumen-normal tissue interface, colorectal luminal surface (CLS)-targeting ligand-functionalized nanoparticles selectively accumulate in CRC tissues without systemic distribution, resulting in successful local CRC therapy. The findings suggest that CLS-targeted lumen-to-tumor delivery can be a suitable strategy for highly CRC-specific drug delivery for precise local CRC therapy.

Large-capacity DNA vectors based on rolling circle amplification with multivalent aptamers delivery copper sulfide for the synergistic treatment of Cancer through chemo/Photothermal/Chemodynamic therapy in vitro.

Developing multifunctional nanomedicines represents a frontier. We have engineered a high-capacity DNA vector basing rolling circle amplification for the delivery of copper sulfide nanoparticles (CuS NPs) and doxorubicin (DOX), coupled with multivalent aptamers (MA) that precisely target tumors, culminating in a multifunctional nanoplatform (RMAL1Cu@DOX), which combines the chemotherapy (CT)/photothermal therapy (PTT)/chemodynamic therapy (CDT). The vector (RMAL1) boasts exceptional biocompatibility and incorporates multiple copy units, enabling the precise loading of numerous CuS NPs, forming RMAL1Cu which possesses a robust photothermal effect and superior Fenton-like catalytic activity, heralding a project of minimally invasive dual-mode (PTT/CDT) therapy. Furthermore, the abundance of G-C of RMAL1 enabled effective DOX encapsulation through π-π interactions to construct RMAL1Cu@DOX. The MA integrated into RMAL1Cu@DOX is pivotal in enhancing the targeting of tumors and in preventing non-specific release of CuS and DOX, enabling an integrated CT/PTT/CDT. Data indicate that 1nM of RMAL1Cu could load 270nM of DOX with an impressive loading capacity of 77%, and modification with MA, its tumor-targeting ability was amplified by 51-fold and significantly bolstered in vitro imaging outcomes, and the synergistic killing of B16 was as 67.3%. This innovative nanoplatform offers a comprehensive and holistic strategy for the treatment of malignant tumors.

Chemistry, manufacturing and controls strategies for using novel excipients in lipid nanoparticles.

Lipid nanoparticles (LNPs) for nucleic acid delivery often use novel lipids as functional excipients to modulate the biodistribution, pharmacokinetics, pharmacodynamics and efficacy of the nucleic acid. Novel excipients used in pharmaceutical products are subject to heightened regulatory scrutiny and often require data packages comparable to an active pharmaceutical ingredient. Although these regulatory requirements may help to ensure patient safety they also create economic and procedural barriers that can disincentivize innovation and delay clinical investigation. Despite the unique structural and functional role of lipid excipients in LNPs, there is limited specific global regulatory guidance, which adds uncertainty and risk to the development of LNPs. In this Perspective we provide an industry view on the chemistry, manufacturing and controls challenges that pharmaceutical companies face in the use of novel lipid excipients at each stage of development, and propose consensus recommendations on how to streamline and clarify development and regulatory expectations.

A Facile Approach To Develop Ion Pair Micelles Satellited Freshly Derived Neutrophils For Targeted Tumor Therapy.

Immune cells show enormous potential for targeted nanoparticle delivery due to their intrinsic tumor-homing skills. However, the immune cells can internalize the nanoparticles, leading to cellular functional impairments, degradation of the nanoparticles, and delayed release of drugs from the immune cells. To address these issues, this study introduces an approach for the synthesis of freshly derived neutrophils (NUs)-based nanocarriers system where the NUs are surfaced by dialdehyde alginate-coated self-assembled micelles loaded with mitoxantrone (MIT) and indocyanine green (ICG) (i.e., dA(MI@IPM)s) for stimuli-responsive tumor-targeted therapy. Here, the dA(MI@IPM)s are not internalized by the NUs, but they are anchored on the membrane of the NUs via distearoylphosphatidylethanolamine-polyethylene glycol-polyethylenimine anchors. Owing to the natural recruitment ability of NUs to the tumor microenvironment, NUs-anchored dA(MI@IPM)s accumulation is higher at the tumor site than free dA(MI@IPM)s, where the dA(MI@IPM)s can readily detach from the NUs to get internalized in the tumor cells. The stimuli-responsive dA(MI@IPM)s disassembles inside the cancer cells upon near-infrared irradiation due to the photosensitizing effect of the loaded ICG, releasing MIT and significantly inhibiting tumor growth. This approach is simple and fast to prepare, opening up exciting possibilities for personalized cancer treatment using patient's autologous NUs.

Current Status of Gout Arthritis: Current Approaches to Gout Arthritis Treatment: Nanoparticles Delivery Systems Approach.

The deposition of monosodium urate (MSU) crystals within joint spaces produces a painful inflammatory condition known as gout, a specific form of arthritis. The condition calls for a combined curative and preventive management model. A new development in the approach to gout is that of NLRP3-targeted biologic agents, such as monoclonal therapies, to provide more accurate treatment by blocking specific pro-inflammatory cytokines. Nanoparticle drug delivery enhances biological availability and delivery to targets, which may increase therapeutic efficacy and decrease general toxicity. The preventive approach again cannot be ignored, mainly keeping up certain modifications in diet and weight, along with pharmacological therapies to reduce uric acid (UA) levels and to decrease the frequency of acute attacks. The advancement of genetic profiling of patients and biomarker discoveries drives the trend towards building individualized medicine and care, quickly gaining ground as the most effective method of delivering treatments to individual patients, moving away from one-size-fits-all treatments. The following paper aims to provide an updated account of the management of gout with a focus on recent developments, in order to enhance these approaches, the quality of life for patients with gout, and the standard of gout treatment.

Lipopolymers as the Basis of Non-Viral Delivery of Therapeutic siRNA Nanoparticles in a Leukemia (MOLM-13) Model.

Small interfering RNA (siRNA) therapy in acute myeloid leukemia (AML) is a promising strategy as the siRNA molecule can specifically target proteins involved in abnormal cell proliferation. The development of a clinically applicable method for delivering siRNA molecules is imperative due to the challenges involved in effectively delivering the siRNA into cells. We investigated the delivery of siRNA to AML MOLM-13 cells with the use of two lipid-substituted polyethyleneimines (PEIs), a commercially available reagent (Prime-Fect) and a recently reported reagent with improved lipid substitution (PEI1.2k-PHPA-Lin9). The siRNAs utilized in this study were targeting the oncogenes FLT3 and KMT2A::MLLT3. Both lipopolymers gave similar-size siRNA complexes (210-220 nm) with positive ζ-potentials (+17 to +25 mV). While the binding efficiency of both lipopolymers to siRNA were similar, PEI1.2k-PHPA-Lin9 complexes were more resistant to heparin-induced dissociation. The quantitative analysis of gene silencing performed by qPCR as well as immunostaining/flow cytometry indicated significant reduction in both FLT3 expression and FLT3 protein after specific siRNA delivery. The desired inhibition of cell growth was attained with both FLT3 and KMT2A::MLLT3 siRNAs, and the combination provided more potent effects in both cell growth and colony formation assays. Induction of apoptosis was confirmed after specific siRNA treatments using the Annexin V assay. Using Luc(+) MOLM-13 cells, the growth of the xenografted cells was shown to be retarded with Prime-Fect-delivered FLT3 siRNA, unlike the siRNA delivered with PEI1.2k-PHPA-Lin9. These results demonstrate the potential of designed lipopolymers in implementing RNAi (via delivery of siRNA) for inhibition of leukemia growth and provide evidence for the feasibility of targeting different oncogenes using siRNA-mediated therapy.

Erratum in: Focused Ultrasound as a Novel Non-Invasive Method for the Delivery of Gold Nanoparticles to Retinal Ganglion Cells.

Erratum in: Focused Ultrasound as a Novel Non-Invasive Method for the Delivery of Gold Nanoparticles to Retinal Ganglion Cells.

Lipid nanoparticles deliver DNA-encoded biologics and induce potent protective immunity

Lipid nanoparticles (LNPs) for mRNA delivery have advanced significantly, but LNP-mediated DNA delivery still faces clinical challenges. This study compared various LNP formulations for delivering DNA-encoded biologics, assessing their expression efficacy and the protective immunity generated by LNP-encapsulated DNA in different models. The LNP formulation used in Moderna’s Spikevax mRNA vaccine (LNP-M) demonstrated a stable nanoparticle structure, high expression efficiency, and low toxicity. Notably, a DNA vaccine encoding the spike protein, delivered via LNP-M, induced stronger antigen-specific antibody and T cell immune responses compared to electroporation. Single-cell RNA sequencing (scRNA-seq) analysis revealed that the LNP-M/pSpike vaccine enhanced CD80 activation signaling in CD8+ T cells, NK cells, macrophages, and DCs, while reducing the immunosuppressive signals. The enrichment of TCR and BCR by LNP-M/pSpike suggested an increase in immune response specificity and diversity. Additionally, LNP-M effectively delivered DNA-encoded antigens, such as mouse PD-L1 and p53R172H, or monoclonal antibodies targeting mouse PD1 and human p53R282W. This approach inhibited tumor growth or metastasis in several mouse models. The long-term anti-tumor effects of LNP-M-delivered anti-p53R282W antibody relied on memory CD8+ T cell responses and enhanced MHC-I signaling from APCs to CD8+ T cells. These results highlight LNP-M as a promising and effective platform for delivering DNA-based vaccines and cancer immunotherapies.

Ionizable Cholesterol Analogs as the Fifth Component of Lipid Nanoparticles for Selective Targeting Delivery of mRNA.

Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential for precise therapeutic outcomes and minimized side effects in various disease models. However, achieving targeted delivery beyond the liver is a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto the head of a cholesterol-like structure and incorporated them as a fifth component into conventional commercial LNPs based on ALC-0315 or SM-102. Selective targeting delivery of mRNA is achieved by adjusting the proportion of the fifth component in the LNP. Specifically, a spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% delivery efficiency, while a lung-targeted 102-Sito-40% formulation achieved up to 78%. Moreover, when this strategy is applied to a self-developed ionizable lipid named U-101 instead of ALC-0315 or SM-102, the targeting delivery efficiencies to the spleen and lungs reach 96 and 71%, respectively. Multiple assessments suggest that inclusion of the fifth component does not compromise LNP stability, as indicated by consistent particle size, polydispersity index (PDI), and encapsulation efficiency. Furthermore, the test results of liver and kidney function and immunogenicity reveal no increase of toxicity in vivo following the introduction of the fifth component. Additional studies on in vitro cytotoxicity, lysosomal escape, and cellular transfection efficiency confirm that the fifth component does not diminish delivery performance. Taken together, the incorporation of ionizable cholesterol analogs leads to targeting of LNP delivery, which features strong organ selectivity, high safety, and suitability for further evaluation.

Development and Evaluation of the Immunogenic Potential of an Unmodified Nucleoside mRNA Vaccine for Herpes Zoster.

Approved mRNA vaccines commonly use sequences modified with pseudouridine to enhance translation efficiency and mRNA stability. However, this modification can result in ribosomal frameshifts, reduced immunogenicity, and higher production costs. This study aimed to explore the potential of unmodified mRNA sequences for varicella-zoster virus (VZV) and evaluate whether codon optimization could overcome the limitations of pseudouridine modification. We utilized artificial intelligence (AI) to design several unmodified gE mRNA sequences for VZV, considering factors such as codon preference and secondary structure. The optimized mRNA sequences were assessed for protein expression levels in vitro and were subsequently used to develop a vaccine, named Vac07, encapsulated in a lipid nanoparticle (LNP) delivery system. The immunogenicity of Vac07 was evaluated in mice. Codon-optimized mRNA sequences showed significantly higher protein expression levels in vitro compared to wild-type (WT) sequences. Vaccination with Vac07 demonstrated immunogenicity in mice that was comparable to, or even superior to, the licensed Shingrix vaccine, characterized by a stronger Th1-biased antibody response and a slightly more robust Th1-type cellular response. Codon-optimized unmodified mRNA sequences may also represent a viable approach for mRNA vaccine development. These optimized sequences have the potential to lower production costs while possibly enhancing the immunogenicity of mRNA vaccines. Vac07, developed using this method, shows promise as a potentially more efficient and cost-effective mRNA vaccine candidate for VZV.

Nanoparticle Association with Brain Cells Is Augmented by Protein Coronas Formed in Cerebrospinal Fluid.

Neuronanomedicine harnesses nanoparticle technology for the treatment of neurological disorders. An unavoidable consequence of nanoparticle delivery to biological systems is the formation of a protein corona on the nanoparticle surface. Despite the well-established influence of the protein corona on nanoparticle behavior and fate, as well as FDA approval of neuro-targeted nanotherapeutics, the effect of a physiologically relevant protein corona on nanoparticle-brain cell interactions is insufficiently explored. Indeed, less than 1% of protein corona studies have investigated protein coronas formed in cerebrospinal fluid (CSF), the fluid surrounding the brain. Herein, we utilize two clinically relevant polymeric nanoparticles (PLGA and PLGA-PEG) to evaluate the formation of serum and CSF protein coronas. LC-MS analysis revealed distinct protein compositions, with selective enrichment/depletion profiles. Enhanced association of CSF precoated particles with brain cells demonstrates the importance of selecting physiologically relevant biological fluids to more accurately study protein corona formation and subsequent nanoparticle-cell interactions, paving the way for improved nanoparticle engineering for in vivo applications.