Recent advances in erythrocyte membrane-camouflaged nanoparticles for the delivery of anti-cancer therapeutics.

INTRODUCTION: Red blood cell (or erythrocyte) membrane-camouflaged nanoparticles (RBC-NPs) not only have a superior circulation life and do not induce accelerated blood clearance but also possess special functions, which offers great potential in cancer therapy. AREAS COVERED: This review focuses on the recent advances of RBC-NPs for delivering various agents to treat cancers in light of their vital role in improving drug delivery. Meanwhile, the construction and in vivo behavior of RBC-NPs are discussed to provide an in-depth understanding of the basis of RBC-NPs for improved cancer drug delivery. EXPERT OPINION: Although RBC-NPs are quite prospective in delivering anti-cancer therapeutics, they are still in their infancy stage and many challenges need to be overcome for successful translation into the clinic. The preparation and modification of RBC membranes, the optimization of coating methods, the scale-up production and the quality control of RBC-NPs, and the drug loading and release should be carefully considered in the clinical translation of RBC-NPs for cancer therapy.

Low-temperature photothermal irradiation triggers alkyl radicals burst for potentiating cancer immunotherapy.

Although low-temperature photothermal therapy (PTT) can sensitize tumors to immune checkpoint inhibition, its efficacy is still restricted in the deep and internal tumors without enough oxygen and lymphocytic infiltration. Non-oxygen-dependent alkyl radicals have been demonstrated to synergistically enhance PTT through up-regulating lipid peroxidation and reactive oxygen species (ROS). Herein, an innovative strategy based on alkyl radicals to augment immunogenetic cell death (ICD) caused by mild PTT was proposed to improve poor efficacy of immunotherapy, which composed of a photothermal material of Chinse ink, an azo-initiator of 2,2-azobis[2-(2-imidazoline-2-acyl)propane]dihydrochloride (AIPH) and a PD-L1 inhibitor of HY19991 (HY). Upon near-infrared-II laser irradiation, low-temperature (<45℃) stimulation induced a high expression of immune checkpoint receptor (PD-L1) in tumors and triggered a large amount alkyl radicals generated by AIPH. Significantly, the alkyl radicals augmented the ICD and increased the recruitment of tumor-infiltrating lymphocytes against tumors after transformation of the immunologically cold tumor microenvironment into hot by mild PTT. The released HY further enhanced the immunotherapy effect by blocking the binding of activated T lymphocytes and PD-L1. In vivo studies exhibited that the all-in-one hydrogel with synergistic mechanisms had an extraordinary ability to reverse the immunosuppressive microenvironment, stimulate innate and adaptive immune responses to eliminate tumors and prevent metastasis.

Molecular insights and novel approaches for targeting tumor metastasis.

In recent years, due to the effective drug delivery and preciseness of tumor sites or microenvironment, the targeted drug delivery approaches have gained ample attention for tumor metastasis therapy. The conventional treatment approaches for metastasis therapy have reported with immense adverse effects because they exhibited maximum probability of killing the carcinogenic cells along with healthy cells. The tumor vasculature, comprising of vasculogenic impressions and angiogenesis, greatly depends upon the growth and metastasis in the tumors. Therefore, various nanocarriers-based delivery approaches for targeting to tumor vasculature have been attempted as efficient and potential approaches for the treatment of tumor metastasis and the associated lesions. Furthermore, the targeted drug delivery approaches have found to be most apt way to overcome from all the limitations and adverse effects associated with the conventional therapies. In this review, various approaches for efficient targeting of pharmacologically active chemotherapeutics against tumor metastasis with the cohesive objectives of prognosis, tracking and therapy are summarized.

Erythrocyte-cancer hybrid membrane-camouflaged melanin nanoparticles for enhancing photothermal therapy efficacy in tumors.

Cell membrane coating has emerged as an intriguing biomimetic strategy to endow nanomaterials with functions and properties inherent to source cells for various biomedical applications. Hybrid membrane of different types of cells could be coated onto nanoparticle surface to achieve additional functions. Herein, we fused red blood cell (RBC) membrane together with MCF-7 cell membrane and fabricated an erythrocyte-cancer (RBC-M) hybrid membrane-camouflaged melanin nanoparticle (Melanin@RBC-M) platform for enhancing therapeutic efficacy of photothermal therapy (PTT). The fused RBC-M hybrid membrane vesicles retained both RBC and MCF-7 cell membrane proteins and the resultant Melanin@RBC-M exhibited prolonged blood circulation and homotypic targeting to source MCF-7 cells simultaneously. Interestingly, increasing MCF-7 membrane components in RBC-M significantly enhanced the homotypic targeting function of Melanin@RBC-M while increasing RBC membrane components in RBC-M effectively reduced the cellular uptake of Melanin@RBC-M by macrophages and improved their circulation time in the blood. After intravenous injection into MCF-7 tumor-bearing athymic nude mice, Melanin@RBC-M with 1:1 membrane protein weight ratio of RBC to MCF-7 exhibited significantly higher tumor accumulation and better PTT efficacy compared with other Melanin@RBC-M with different membrane protein weight ratios as well as pristine melanin nanoparticles, due to the optimal balance between prolonged blood circulation and homotypic targeting. In addition, in vitro photoacoustic results revealed that Melanin@RBC-M had a photoacoustic signal enhancement with the increase of nanoparticle size (64 → 148 nm) and the photoacoustic amplitudes increased linearly with nanoparticle concentration at the excitation wavelength ranged from 680 nm to 800 nm, which could be used for quantification of Melanin@RBC-M in vivo. Looking forward, coating hybrid membrane onto nanoparticles could add flexibility and controllability in enhancing nanoparticles functionality and offer new opportunities for biomedical applications.

Enhanced photothermal therapy of biomimetic polypyrrole nanoparticles through improving blood flow perfusion.

In this study, we reported a strategy to improve delivery efficiency of a long-circulation biomimetic photothermal nanoagent for enhanced photothermal therapy through selectively dilating tumor vasculature. By using a simply nanocoating technology, a biomimetic layer of natural red blood cell (RBC) membranes was camouflaged on the surface of photothermal polypyrrole nanoparticles (PPy@RBC NPs). The erythrocyte-mimicking PPy NPs inherited the immune evasion ability from natural RBC resulting in superior prolonged blood retention time. Additionally, excellent photothermal and photoacoustic imaging functionalities were all retained attributing to PPy NPs cores. To further improve the photothermal outcome, the endothelin A (ETA) receptor antagonist BQ123 was jointly employed to regulate tumor microenvironment. The BQ123 could induce tumor vascular relaxation and increase blood flow perfusion through modulating an ET-1/ETA transduction pathway and blocking the ETA receptor, whereas the vessel perfusion of normal tissues was not altered. Through our well-designed tactic, the concentration of biomimetic PPy NPs in tumor site was significantly improved when administered systematically. The study documented that the antitumor efficiency of biomimetic PPy NPs combined with specific antagonist BQ123 was particularly prominent and was superior to biomimetic PPy NPs (P < 0.05) and PEGylated PPy NPs with BQ123 (P < 0.01), showing that the greatly enhanced photothermal treatment could be achieved with low-dose administration of photothermal agents. Our findings would provide a promising procedure for other similar enhanced photothermal treatment by blocking ETA receptor to dramatically increase the delivery of biomimetic photothermal nanomaterials.

Red blood cell membrane-camouflaged melanin nanoparticles for enhanced photothermal therapy.

Photothermal therapy (PTT) has represented a promising noninvasive approach for cancer treatment in recent years. However, there still remain challenges in developing non-toxic and biodegradable biomaterials with high photothermal efficiency in vivo. Herein, we explored natural melanin nanoparticles extracted from living cuttlefish as effective photothermal agents and developed red blood cell (RBC) membrane-camouflaged melanin (Melanin@RBC) nanoparticles as a platform for in vivo antitumor PTT. The as-obtained natural melanin nanoparticles demonstrated strong absorption at NIR region, higher photothermal conversion efficiency (∼40%) than synthesized melanin-like polydopamine nanoparticles (∼29%), as well as favorable biocompatibility and biodegradability. It was shown that RBC membrane coating on melanin nanoparticles retained their excellent photothermal property, enhanced their blood retention and effectively improved their accumulation at tumor sites. With the guidance of their inherited photoacoustic imaging capability, optimal accumulation of Melanin@RBC at tumors was achieved around 4 h post intravenous injection. Upon irradiation by an 808-nm laser, the developed Melanin@RBC nanoparticles exhibited significantly higher PTT efficacy than that of bare melanin nanoparticles in A549 tumor-bearing mice. Given that both melanin nanoparticles and RBC membrane are native biomaterials, the developed Melanin@RBC platform could have great potential in clinics for anticancer PTT.

Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease.

Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of ß-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as bFGF to enter the CNS and play the therapeutic role.

Targeting mesoporous silica-encapsulated gold nanorods for chemo-photothermal therapy with near-infrared radiation.

Mesoporous silica-encapsulated gold nanorods (GNRs@mSiO(2)) have great potential both in photothermal therapy and drug delivery. In this paper, we firstly developed GNRs@mSiO(2) as a synergistic therapy tool for delivery heat and drug to the tumorigenic region. We studied the ablation of tumor both in vitro and in vivo by the combination of photothermal therapy and chemotherapy using doxorubicin (DOX)-loaded GNRs@mSiO(2). Significantly greater cell killing was observed when A549 cells incubated with DOX-loaded GNRs@mSiO(2) were irradiated with near-infrared (NIR) illumination, attributable to both GNRs@mSiO(2)-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. We then performed in vivo therapy studies and observed a promising tumor treatment. Compared with chemotherapy or photothermal treatment alone, the combined treatment showed a synergistic effect, resulting in higher therapeutic efficacy. Furthermore, the lower systematic toxicity of GNRs@mSiO(2) has been validated.