Regulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery.

The dynamic protein corona formed on nanocarriers has been revealed to strongly affect their in vivo behaviors. Precisely manipulating the formation of protein corona on nanocarriers may provide an alternative impetus for specific drug delivery. Herein, we explore the role of glycosylated polyhydroxy polymer-modified nanovesicles (CP-LVs) with different amino/hydroxyl ratios in protein corona formation and evolution. CP-LVs with an amino/hydroxyl ratio of approximately 0.4 (CP1-LVs) are found to efficiently suppress immunoglobulin adsorption in blood and livers, resulting in prolonged circulation. Moreover, CP1-LVs adsorb abundant tumor distinctive proteins, such as CD44 and osteopontin in tumor interstitial fluids, mediating selective tumor cell internalization. The proteins corona transformation specific to the environment appears to be affected by the electrostatic interaction between CP-LVs and proteins with diverse isoelectric points. Benefiting from surface modification-mediated protein corona regulation, paclitaxel-loaded CP1-LVs demonstrate superior antitumor efficacy to PEGylated liposomes. Our work offers a perspective on rational surface-design of nanocarriers to modulate the protein corona formation for efficient drug delivery.

Cell Membrane-Camouflaged Nanocarriers with Biomimetic Deformability of Erythrocytes for Ultralong Circulation and Enhanced Cancer Therapy.

Despite considerable advancements in cell membrane-camouflaged nanocarriers to leverage natural cell functions, artificial nanocarriers that can accurately mimic both the biological and physical properties of cells are urgently needed. Herein, inspired by the important effect of the stiffness and deformability of natural red blood cells (RBCs) on their life span and flowing through narrow vessels, we report the construction of RBC membrane-camouflaged nanocarriers that can mimic RBCs at different life stages and study how the deformability of RBC-derived nanocarriers affects their biological behaviors. RBC membrane-coated elastic poly(ethylene glycol) diacrylate hydrogel nanoparticles (RBC-ENPs) simulating dynamic RBCs exhibited high immunocompatibility with minimum immunoglobulin adsorption in the surface protein corona, resulting in reduced opsonization in macrophages and ultralong circulation. Furthermore, RBC-ENPs can deform like RBCs and achieve excellent diffusion in tumor extracellular matrix, leading to improved multicellular spheroid penetration and tumor tissue accumulation. In mouse cancer models, doxorubicin-loaded RBC-ENPs demonstrated superior antitumor efficacy to the first-line chemotherapeutic drug PEGylated doxorubicin liposomes. Our work highlights that tuning the physical properties of cell membrane-derived nanocarriers may offer an alternative approach for the bionic design of nanomedicines in the future.

Tumour-derived extracellular vesicle membrane hybrid lipid nanovesicles enhance siRNA delivery by tumour-homing and intracellular freeway transportation.

Extracellular vesicles (EVs) have been proved a promising small interfering RNA (siRNA) delivery vehicle to mediate gene-silencing. Tumour-derived extracellular vesicles (TDEVs) as genetic exchange vectors in the tumour microenvironment, enable intercellular communication for a wide range of endogenous cargo molecules, such as RNAs and proteins. However, the oncogenic cargo of TDEVs limits their application in siRNA delivery for cancer therapy. Herein, we isolated TDEVs from hepatocellular carcinoma (HCC) cells and derived TDEV membranes by abandoning their content. Innovative TDEV membrane hybrid lipid nanovesicles (LEVs) were then fabricated by fusion of TDEV membranes and phospholipids to realize precise delivery to tumours and highly efficient transfection of siRNA. The TDEV membranes endow LEVs with 'homing' targeting ability, facilitating specific internalisation into parent HCC cells primarily through heparan sulfate proteoglycan-mediated pathways. Unlike conventional lipid-based nanovesicles, LEVs can bypass the endosomal degradation pathway, boost the delivery of siRNA through the Golgi and endoplasmic reticulum (ER) intracellular 'freeway' transportation, achieving a 1.7-fold improvement in siRNA transfection efficiency compared with liposomes. Additionally, siRNA loaded LEVs were demonstrated to enhance the antitumour efficacy in HCC bearing mice through effective gene silencing in the tumour sites. Our results highlight the potential application of the TDEV membrane-derived nanovesicles as an advanced siRNA delivery strategy for cancer therapy.

Detachable Liposomes Combined Immunochemotherapy for Enhanced Triple-Negative Breast Cancer Treatment through Reprogramming of Tumor-Associated Macrophages.

Triple-negative breast cancer (TNBC) is an aggressive disease with a high recurrence rate and poor outcomes in clinic. In this study, inspired by the enriched innate immune cell type tumor-associated macrophages (TAMs) in TNBC, we proposed a matrix metalloprotease 2 (MMP2) responsive integrated immunochemotherapeutic strategy to deliver paclitaxel (PTX) and anti-CD47 (aCD47) by detachable immune liposomes (ILips). In the TNBC microenvironment, the "two-in-one" ILips facilitated MMP2-responsive release of aCD47 to efficiently polarize M2 macrophages toward the M1 phenotype to enhance phagocytosis against tumor cells and activate the systemic T cell immune response. Together with the immune effect, the detached PTX-loaded liposomes were internalized in MDA-MB-231 cells to synergistically inhibit tumor cell proliferation and metastasis. In the TNBC-bearing mouse model, PTX-loaded ILips demonstrated superior antitumor efficacy against TNBC and inhibited tumor recurrence. Our integrated strategy represents a promising approach to synchronously enhance immune response and tumor-killing effects, improving the therapeutic efficacy against TNBC.

Chitosan oligosaccharide modified liposomes enhance lung cancer delivery of paclitaxel.

Lung cancer is one of the leading causes of cancer-related death worldwide. Various therapeutic failed in the effective treatment of the lung cancer due to their limited accumulation and exposure in tumors. In order to promote the chemotherapeutics delivery to lung tumor, we introduced chitosan oligosaccharide (CSO) modification on the liposomes. CSO conjugated Pluronic P123 polymers with different CSO grafting amounts, called as CP50 and CP20, were synthesized and used to prepare CSO modified liposomes (CP50-LSs and CP20-LSs). CP50-LSs and CP20-LSs displayed significantly enhanced cellular uptake in A549 cells in vitro as well as superior tumor accumulation in vivo compared with non-CSO modified liposomes (P-LSs). This phenomenon was related to the increased affinity between CSO modified liposomes and tumor cells following massive adsorption of collagen, which was highly expressed in lung tumors. In the A549 tumor-bearing mouse model, intravenous injection of paclitaxel (PTX)-loaded CP50-LSs every 3 days for 21 days resulted in optimal antitumor therapeutic performance with an inhibition rate of 86.4%. These results reveal that CSO modification provides promising applicability for nanomedicine design in the lung cancer treatment.