Redox‐Responsive and Drug‐Embedded Silica Nanoparticles with Unique Self‐Destruction Features for Efficient Gene/Drug Codelivery

The development of advanced gene/drug codelivery carriers with stimuli‐responsive release manner for complementary cancer therapy is desirable. In this study, novel disulfide‐bridged and doxorubicin (DOX)‐embedded degradable silica nanoparticles (DS‐DOX) with unique self‐destruction features are synthesized by a facile one‐pot method. In order to realize codelivery of genes and drugs, the surface of DS‐DOX nanoparticles is readily functionalized with the assembled polycation (CD‐PGEA), comprising one β‐cyclodextrin core and two ethanolamine‐functionalized poly(glycidyl methacrylate) arms, to achieve DS‐DOX‐PGEA. The redox‐responsive self‐destruction behavior of DS‐DOX imparts DS‐DOX‐PGEA with a better ability to release anticancer drug DOX, while the low‐toxic hydroxyl‐rich CD‐PGEA brushes can efficiently deliver genes for cancer treatment. Very interestingly, the degradation process of DS‐DOX starts from the outside, while the destruction of the degradable silica (DS) nanoparticles without DOX begins from the center of the nanoparticles. The embedded DOX inside the DS‐DOX nanoparticles can significantly influence the structures and facilitate the cellular uptake and the subsequent gene transfection. The as‐developed DS‐DOX‐PGEA nanostructure with coordinating biodegradability, stimuli‐responsiveness, and controlled release manner might be desirable gene/drug codelivery carriers for clinical cancer treatment.     

An Integrated Therapeutic Delivery System for Enhanced Treatment of Hepatocellular Carcinoma

Nanomaterials hold promise for the treatment of human carcinomas but integrating multiple functions into a single drug carrier system remains challenging. Herein, an integrated therapeutic delivery system for human hepatocellular carcinoma (HCC) treatment is reported, which is based on rhodamine B (RhB) end‐labeled cationic poly[2‐(dimethylamino)ethyl methacrylate] (PDMAEMA) and hydrophobic poly(3‐azido‐2‐hydroxypropyl methacrylate) (PGMA‐N₃) segments equipped with a covalently bound galactose. This biocompatible and safe platform RhB‐PDMAEMA25‐c‐PGMA50‐Gal micelles (Gal‐micelles) offers four advantages: (1) Galactose ligands enhance cellular uptake by targeting the asialoglycoprotein receptor (ASGPR) that is overexpressed on HCC cell lines surfaces; (2) RhB end‐labeling facilitates real‐time imaging for tracking both in vitro and in vivo; (3) the acidic tumor microenvironment protonates the carrier system for efficient drug release as well as gene transfection, (4) codelivery of anticancer drug doxorubicin (DOX) and B‐cell lymphoma 2 small interfering RNA (Bcl‐2 siRNA) works synergistically against tumor growth in both subcutaneous and orthotopic HCC bearing mouse models. This integrated therapeutic delivery system holds potential for future clinical HCC treatment.     

Properties of Native High‐Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles

Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High‐density lipoproteins (HDLs) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) load single‐stranded RNA; 2) are anionic, which requires charge reconciliation between the RNA and HDL, and 3) actively target scavenger receptor type B‐1 (SR‐B1) to deliver RNA. Emphasizing these particular parameters, templated lipoprotein particles (TLP), mimics of spherical HDLs, are employed and are self‐assembled with single‐stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA‐TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA‐TLPs actively target SR‐B1 to potently reduce androgen receptor and enhancer of zeste homolog 2 proteins in multiple cancer cell lines. Systemic administration of siRNA‐TLPs demonstrated no off‐target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single‐stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR‐B1.     

Tumor‐Microenvironment‐Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer

Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment‐adaptive nanoparticle co‐loading paclitaxel (PTX) and the anti‐metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH‐sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra‐tumor accumulation of both PTX and siRNA in the 4T1 tumor‐bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid‐triggered drug release in endo/lysosomes is achieved through the pH‐sensitive core. As a result, the MMP/pH dual‐sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor‐microenvironment‐adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.     

Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

Combination cancer immunotherapy has shown promising potential for simultaneously eliciting antitumor immunity and modulating the immunosuppressive tumor microenvironment (ITM). However, combination immunotherapy with multiple regimens suffers from the varied chemo‐physical properties and inconsistent pharmacokinetic profiles of the different therapeutics. To achieve tumor‐specific codelivery of the immune modulators, an indocyanine green (ICG)‐templated self‐assembly strategy for preparing dual drug‐loaded two‐in‐one nanomedicine is reported. ICG‐templated self‐assembly of paclitaxel (PTX) nanoparticles (ISPN), and the application of ISPN for combination immunotherapy of the triple negative breast cancer (TNBC) are demonstrated. The ISPN show satisfied colloidal stability and high efficacy for tumor‐specific codelivery of ICG and PTX through the enhanced tumor permeability and retention effect. Upon laser irradiation, the ICG component of ISPN highly efficiently induces immunogenic cell death of the tumor cells via activating antitumor immune response through photodynamic therapy. Meanwhile, PTX delivered by ISPN suppresses the regulatory T lymphocytes (T_regs) to combat ITM. The combination treatment of TNBC with ISPN and αPD‐L1‐medaited immune checkpoint blockade therapy displays a synergistic effect on tumor regression, metastasis inhibition, and recurrence prevention. Overall, the ICG‐templated nanomedicine may represent a robust nanoplatform for combination immunotherapy.     

Nano‐Self‐Assembly of Nucleic Acids Capable of Transfection without a Gene Carrier

Nonviral gene carriers based on electrostatic interaction, encapsulation, or absorption require a large amount of polymer carrier to achieve reasonable transfection efficiencies. With cationic nanoparticles, for example, genes interact only with the surface of the nanoparticles, resulting in a low surface area to volume ratio (SA/V = 3/r). A large volume of carrier, therefore, is required to deliver a small copy number of genes. In this study, it is demonstrated that a nano‐self‐assembly of nucleic acids transfects itself into cells spontaneously, without the need for a gene carrier. The cellular uptake of this nanoassembly occurs through a number of endocytosis mechanisms. Once within the cell, the nanoassembly can escape endolysosomal vesicles and facilitate gene transfection. This nano‐self‐assembly consisting of zinc and plasmid DNA or siRNA, termed the Zn/DNA or Zn/siRNA nanocluster, is formed through the binding of Zn²⁺ ions to the phosphate groups of nucleic acids. The method described in this paper represents a new platform for carrier‐free gene delivery that can be used to deliver any plasmid DNA or siRNA without the requirement for a specific modification in the nucleic acids or complicated steps to prepare dense particles.     

Structure‐Invertible Nanoparticles for Triggered Co‐Delivery of Nucleic Acids and Hydrophobic Drugs for Combination Cancer Therapy

Here, a new type of structure‐invertible, redox‐responsive polymeric nanoparticle for the efficient co‐delivery of nucleic acids and hydrophobic drugs in vitro and in vivo is reported for the first time, to combat the major challenges facing combination cancer therapy. The co‐delivery vector, which is prepared by conjugating branched poly(ethylene glycol) with dendrimers of two generations (G2) through disulfide linkages, is able to complex nucleic acids and load hydrophobic drugs with high loading capacity through structure inversion. The cleavage of disulfide linkages at intracellular glutathione‐rich reduction environment significantly decreases the cytotoxicity, and promotes more efficient drug release and gene transfection in vitro and in vivo. The co‐delivery carrier also displays enhanced endosomal escape capability and improved serum stability in vitro as compared with G2, and exhibits prolonged residence time and stronger transfection activity in vivo. Most importantly, co‐delivery of doxorubicin (DOX) and B‐cell lymphoma 2 (Bcl‐2) small interfering RNA (siRNA) exerts a combinational effect against tumor growth in murine tumor models in vivo, which is much more effective than either DOX or Bcl‐2 siRNA‐based monotherapy. The structure‐invertible nanoparticles may constitute a promising stimuli‐responsive system for the efficacious co‐delivery of multiple cargoes in future clinical applications of combination cancer therapies.     

High‐Drug‐Loading Mesoporous Silica Nanorods with Reduced Toxicity for Precise Cancer Therapy against Nasopharyngeal Carcinoma

Nanorod‐based drug delivery systems have attracted great interest because of their enhanced cell internalization capacity and improved drug loading property. Herein, novel mesoporous silica nanorods (MSNRs) with different lengths are synthesized and used as nanocarriers to achieve higher drug loading and anticancer activity. As expected, MSNRs‐based drug delivery systems can effectively enhance the loading capacity of drugs and penetrate into tumor cells more rapidly than spherical nanoparticles due to their greater surface area and trans‐membrane transporting rates. Interestingly, these tailored MSNRs also enhance the cellular uptake of doxorubicin (DOX) in cancer cells, thus significantly enhancing its anticancer efficacy for hundreds of times by inducing of cell apoptosis. Internalized MSNRs‐DOX triggers intracellular reactive oxygen species (ROS) overproduction, which subsequently activates p53 and mitogen‐activated protein kinases (MAPKs) pathways to promote cell apoptosis. MSNRs‐DOX nanosystem also shows prolonged blood circulation time in vivo. In addition, MSNRs‐DOX significantly inhibits in vivo tumor growth in nude mice model and effectively reduced its in vivo toxicity. Therefore, this study provides an effective and safe strategy for designing chemotherapeutic agents for precise cancer therapy.     

Ultralong Circulating Lollipop‐Like Nanoparticles Assembled with Gossypol,Doxorubicin, and Polydopamine via π–π Stacking for Synergistic Tumor Therapy

Long blood circulation in vivo remains a challenge to dual‐drug‐loaded nanocarriers for synergistic chemotherapy. Herein, a novel strategy to prepare lollipop‐like dual‐drug‐loaded nanoparticles (DOX–PDA–gossypol NPs) is developed based on the self‐assembly of gossypol, doxorubicin (DOX), and polydopamine (PDA) via π–π stacking. Dopamine polymerizes to PDA and fills the gaps between the gossypol and DOX molecules to form the super compact long‐circulating nanoparticles. The DOX–PDA–gossypol NPs show a suitable particle size of 59.6 ± 9.6 nm, high drug loading of 91%, superb stability, high maximum‐tolerated dose (MTD) of over 60 mg kg^‐1, and negligible toxicity. These NPs also exhibit pH‐dependent drug release and low combination index (0.23). Notably, they show dramatically ultralong blood circulation (>192 h) with elimination half times 458‐fold and 258‐fold longer than that of free DOX and free gossypol, respectively. These values are markedly higher than most of the reported results. Therefore, the DOX–PDA–gossypol NPs have a high tumor accumulation of 12% remaining on the 8th day postinjection. This characteristic contributes to the excellent tumor comprehensive synergistic therapeutic efficacy (TIR > 90%) with low administration dosage and is benefitted for widening the drug therapeutic window. Thus, the proposed strategy has remarkable potential for tumor synergistic therapy.     

Multifunctional DNA Polycatenane Nanocarriers for Synergistic Targeted Therapy of Multidrug‐Resistant Human Leukemia

Chemotherapy, as one of the principal modalities for cancer therapy, is limited by its inefficient delivery, serious side effects as well as multidrug resistance (MDR). Herein, multifunctional aptamer‐tethered deoxyribonucleic acids (DNA) polycatenanes (AptDPCs) is reported to combat MDR human leukemia. By rational design, the DNA polycatenanes (DPCs) are first constructed by a one‐step self‐assembly approach, during which DPCs are incorporated with fluorophores for bioimaging, abundant doxorubicin (DOX) intercalation sites for drug delivery, and antisense oligonucleotides (AS ODNs) for inhibiting the expression of P‐glycoprotein (P‐gp) and further reversing MDR. In addition, to endow the DPCs with specific recognition toward the target cancer cells and high purity, aptamers are tethered to the DPCs via the magnetic separation method based on the toehold‐mediated strand displacement (TMSD) reaction, which not only improves the purity and reproducibility of the AptDPCs, but also realizes the recycle of magnetic carriers. The results confirm that the AptDPCs can deliver drugs and AS ODNs into the target cancer cells and synergistically inhibit the MDR tumor growth without apparent systematic toxicity. The proposed AptDPC‐based drug delivery system can effectively reduce side effects and reverse MDR, which provides a promising platform for codelivery of therapeutic genes and chemodrugs in targeted cancer therapy.     

Ribonucleoprotein: A Biomimetic Platform for Targeted siRNA Delivery

Many small interfering RNA (siRNA) carriers have been developed over the years, mostly based on cationic lipids and polymers that can condense siRNA into nanoparticle complexes and aid in endosomal escape. In comparison, development of charge‐neutral siRNA carriers to avoid or reduce nonspecific binding, aggregation, and toxicity is limited, due to a lack of mechanisms for carrier‐siRNA association beyond electrostatic interaction. Here, a unique, charge‐neutral, biomimetic platform is reported, mimicking the natural state of functional RNA, ribonucleoprotein (RNP). This RNP architecture is simple to make, precise in assembly stoichiometry, stable in serum, and biocompatible. Gene knockdown is achieved in vitro and in vivo, demonstrating excellent potential for translation.     

Programmed Multiresponsive Vesicles for Enhanced Tumor Penetration and Combination Therapy of Triple‐Negative Breast Cancer

Nanomedicine is a promising approach for combination chemotherapy of triple‐negative breast cancer (TNBC). However, the therapeutic efficacy of nanoparticulate drugs is suppressed by a series of biological barriers. The authors herein present a programmed stimuli‐responsive liposomal vesicle to overcome the sequential barriers for enhanced TNBC therapy. The intelligent vesicles are engineered by integrating an enzyme‐cleavable polyethylene glycol (PEG) corona, a light‐responsive photosensitizer pheophorbide a (PPa), and a temperature‐sensitive liposome (TSL) into a single nanoplatform. The resultant enzyme, light, and temperature multisensitive liposome (ELTSL) is sequentially coloaded with a lipophilic oxaliplatin prodrug of hexadecyl‐oxaliplatin carboxylic acid (HOC) and hydrophilic doxorubicin hydrochloride (DOX). Dual drug‐loaded ELTSL displays enhanced tumor penetration and increased cellular uptake upon matrix metalloproteinase 2 mediated cleavage of the PEG corona. Under NIR laser irradiation, PPa induces mild hyperthermia effect to trigger ultrafast drug release in the tumor cells. In combination with PPa‐mediated photodynamic therapy, HOC and DOX coloaded ELTSL show significantly improved antitumor efficacy than monotherapy. Given the clinically translatable potential of the liposomal vesicles, ELTSL might represent a promising nanoplatform for combination TNBC therapy.     

Redox Sensitive Hyaluronic Acid‐Decorated Graphene Oxide for Photothermally Controlled Tumor‐Cytoplasm‐Selective Rapid Drug Delivery

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox‐sensitive, hyaluronic acid‐decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm‐specific rapid delivery using near‐infrared (NIR) irradiation controlled endo/lysosome disruption and redox‐triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox‐sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug‐loading capacity for aromatic molecules, HA receptor‐mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox‐dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA‐receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm‐specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox‐triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment.     

A Multifunctional Nanoplatform against Multidrug Resistant Cancer: Merging the Best of Targeted Chemo/Gene/Photothermal Therapy

Synergistic therapy that combines chemo‐, gene‐, or photothermal means shows great potential for enhancing the therapeutic effects on cancers. Tumor‐targeted nanoparticles based on a doxorubicin (DOX)‐gated mesoporous silica nanocore (MSN) encapsulated with permeability glycoprotein (P‐gp) small interfering RNA (siRNA) and a polydopamine (PDA) outer layer for DOX loading and folic acid decoration are designed. The multifunctional nanoplatform tactfully integrates chemo‐ (DOX), gene‐ (P‐gp siRNA), and photothermal (PDA layer) substances in one system. In vitro results reveal that DOX release behaviors are both pH‐ and thermal‐responsive and the release of co‐delivered P‐gp siRNA is also pH‐dependent due to the pH‐cleavable DOX gatekeeper on MSN. In addition, due to the near‐infrared light‐responsive PDA outer layer and folic acid conjugation, the nanoparticles exhibit outstanding photothermal activity and selective cell targeting ability. Subsequently, in vitro and in vivo antitumor experiments both demonstrate the enhanced antitumor efficacy of the multifunctional nanoparticles, indicating the significance of synergistic therapy combining chemo‐, gene‐, and photothermal treatments in one system.     

Dual Stimuli‐Responsive Supramolecular Polypeptide‐Based Hydrogel and Reverse Micellar Hydrogel Mediated by Host–Guest Chemistry

Versatile strategies are currently being discovered for the fabrication of synthetic polypeptide‐based hybrid hydrogels, which have potential applications in polymer therapeutics and regenerative medicine. Herein, a new concept—the reverse micellar hydrogel—is introduced, and a versatile strategy is provided for fabricating supramolecular polypeptide‐based normal micellar hydrogel and reverse micellar hydrogels from the same polypeptide‐based copolymer via the cooperation of host–guest chemistry and hydrogen‐bonding interactions. The supramolecular hydrogels are thoroughly characterized, and a mechanism for their self‐assembly is proposed. These hydrogels can respond to dual stimuli—temperature and pH—and their mechanical and controlled drug‐release properties can be tuned by the copolymer topology and the polypeptide composition. The reverse micellar hydrogel can load 10% of the anticancer drug doxorubicin hydrochloride (DOX) and sustain DOX release for 45 days, indicating that it could be useful as an injectable drug delivery system.     

Stepwise Drug‐Release Behavior of Onion‐Like Vesicles Generated from Emulsification‐Induced Assembly of Semicrystalline Polymer Amphiphiles

Tailoring unique nanostructures of biocompatible and degradable polymers and the consequent elucidation of shape effects in drug delivery open tremendous opportunities not only to broaden their biomedical applications but also to identify new directions for the design of nanomedicine. Cellular organelles provide the basic structural and functional motif for the development of novel artificial nanoplatforms. Herein, aqueous onion‐like vesicles structurally mimicking multicompartmentalized cellular organelles by exhibiting exquisite control over the molecular assembly of poly(ethylene oxide)‐block‐poly(ε‐caprolactone) (PEO‐b‐PCL) semicrystalline amphiphiles are reported. Compared to in situ self‐assembly, emulsification‐induced assembly endows the resulting nanoaggregates of PEO‐b‐PCL with structural diversity such as helical ribbons and onion‐like vesicles through the molecular packing modification in the hydrophobic core with a reduction of inherent crystalline character of PCL. In particular, onion‐like vesicles composed of alternating walls and water channels are interpreted by nanometer‐scale 3D visualization via cryogenic‐electron tomo­graphy (cryo‐ET). Interestingly, the nature of the multi‐walled vesicles results in high drug‐loading capacity and stepwise drug release through hydrolytic cleavage of the PCL block. The crystalline arrangement of PCL at the molecular scale and the spatial organization of assembled structure at the nanoscale significantly affect the drug‐release behavior of PEO‐b‐PCL nanovehicles.     

Matrix Metalloproteinase Responsive,Proximity‐Activated Polymeric Nanoparticles for siRNA Delivery

Small interfering RNA (siRNA) has significant potential to evolve into a new class of pharmaceutical inhibitors, but technologies that enable robust, tissue‐specific intracellular delivery must be developed before effective clinical translation can be achieved. A pH‐responsive, smart polymeric nanoparticle (SPN) with matrix metalloproteinase (MMP)‐7‐dependent proximity‐activated targeting (PAT) is described here. The PAT‐SPN is designed to trigger cellular uptake and cytosolic delivery of siRNA once activated by MMP‐7, an enzyme whose overexpression is a hallmark of cancer initiation and progression. The PAT‐SPN is composed of a corona‐forming polyethylene glycol (PEG) block, an MMP‐7‐cleavable peptide, a cationic siRNA‐condensing block, and a pH‐responsive, endosomolytic terpolymer block that drives self‐assembly and forms the PAT‐SPN core. With this novel design, the PEG corona shields cellular interactions until it is cleaved in MMP‐7‐rich environments, shifting the SPN ζ‐potential from +5.8 to +14.4 mV and triggering a 2.5 fold increase in carrier internalization. The PAT‐SPN exhibits pH‐dependent membrane disruptive behavior that enables siRNA escape from endo‐lysosomal pathways. Intracellular siRNA delivery and knockdown of the model enzyme luciferase in R221A‐Luc mammary tumor cells is significantly increased by MMP‐7 pre‐activation (p < 0.05). These combined data indicate that the PAT‐SPN provides a promising new platform for tissue‐specific, proximity‐activated siRNA delivery to MMP‐rich pathological environments.     

Supramolecular Photothermal Nanomaterials as an Emerging Paradigm toward Precision Cancer Therapy

The concept of the “supramolecular photothermal effects” refers to the collection property and photothermal conversion efficiency resulting from the supramolecular assembly of molecular photothermal sensitizers. This review considers organic supramolecular photothermal materials assembled at the nanoscale via various molecular self‐assembly strategies and associated with the organization of multiple noncovalent interactions. In these materials, the individual photosensitizer molecules are typically aggregated through self‐assembly in a certain form that exhibits enhanced biostability, increased photothermal conversion efficiency with photoluminescence quenching, and improved photothermal therapeutic effects in comparison with those of the monomeric photosensitizer molecules. These supramolecular photothermal effects are controlled or influenced by intermolecular noncovalent interactions, especially the hydrophobic effects, which are distinct from the mechanisms of conventional sensitizer molecules and polymers and inorganic photothermal agents. A focus lies on how self‐assembly strategies give rise to supramolecular photothermal effects, including polymer and protein fabrication, small molecule self‐assembly, and the construction of donor–acceptor binary systems. Emphases are placed on the rational design of supramolecular photothermal nanomaterials, drug delivery, and in vivo photothermal therapeutic effects. Finally, the key challenges and promising prospects of these supramolecular photothermal nanomaterials in terms of both technical advances and clinical translation are discussed.     

NIR/ROS‐Responsive Black Phosphorus QD Vesicles as Immunoadjuvant Carrier for Specific Cancer Photodynamic Immunotherapy

2D black phosphorus (BP) nanosheets and BP quantum dots (BPQD), as two main material styles of BP, are widely used in the biomedical filed. However, few stimuli‐responsive BP nanocarriers are reported to meet the need of nanomedicine. Herein, near‐infrared region/reactive oxygen species (NIR/ROS) sensitive BPQD vesicles (BPNVs) are prepared by self‐assembly of amphiphilic BPQDs grafted with polyethylene glycol and ROS sensitive poly(propylene sulfide) (PPS). BPNVs exhibit enhanced photo‐absorption in the NIR region, and have high loading efficiency of immunoadjuvant CpG oligodeoxynucleotides (CpG ODNs) in the cavity of the BPNVs. Upon NIR laser irradiation, high levels of ROS are generated from BPNVs to trigger the change of hydrophobic PPS to hydrophilic polymers, leading to disassembly of the vesicles to BPQDs. In this manner, the BPNVs show synergistic photodynamic therapy combined with immunotherapy, due to simultaneous release of small BPQDs with deep tumor penetration and CpG with enhanced immunotherapy. The BPNVs‐CpG achieves potent photodynamic immunotherapy in vivo, in addition to block distant tumor growth and metastasis.     

Highly Scalable,Closed‐Loop Synthesis of Drug‐Loaded,Layer‐by‐Layer Nanoparticles

Layer‐by‐layer (LbL) self‐assembly is a versatile technique from which multi­component and stimuli‐responsive nanoscale drug‐carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, a generalizable method for increasing throughput with LbL assembly is described by using highly scalable, closed‐loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid‐polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. The cytotoxicity, shelf life, and long‐term storage of LbL nanoparticles produced using this approach are explored. It is found that LbL coated systems can be reliably and rapidly produced: specifically, LbL‐modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug‐carriers that show low toxicity and are amenable to clinically relevant storage conditions.