Charge‐Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery

DNA‐toxin anticancer drugs target nuclear DNA or its associated enzymes to elicit their pharmaceutical effects, but cancer cells have not only membrane‐associated but also many intracellular drug‐resistance mechanisms that limit their nuclear localization. Thus, delivering such drugs directly to the nucleus would bypass the drug‐resistance barriers. The cationic polymer poly(L ‐lysine) (PLL) is capable of nuclear localization and may be used as a drug carrier for nuclear drug delivery, but its cationic charges make it toxic and cause problems in in‐vivo applications. Herein, PLL is used to demonstrate a pH‐triggered charge‐reversal carrier to solve this problem. PLL's primary amines are amidized as acid‐labile β‐carboxylic amides (PLL/amide). The negatively charged PLL/amide has a very low toxicity and low interaction with cells and, therefore, may be used in vivo. But once in cancer cells' acidic lysosomes, the acid‐labile amides hydrolyze into primary amines. The regenerated PLL escapes from the lysosomes and traverses into the nucleus. A cancer‐cell targeted nuclear‐localization polymer–drug conjugate has, thereby, been developed by introducing folic‐acid targeting groups and an anticancer drug camptothecin (CPT) to PLL/amide (FA‐PLL/amide‐CPT). The conjugate efficiently enters folate‐receptor overexpressing cancer cells and traverses to their nuclei. The CPT conjugated to the carrier by intracellular cleavable disulfide bonds shows much improved cytotoxicity.     

A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ‐Fe₂O₃ magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginine‐glycine‐aspartic acid‐l ‐tumor necrosis factor‐related apoptosis‐inducing ligand (RGD‐l ‐TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD‐l ‐TRAIL@MMBs. Such RGD‐l ‐TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD‐l ‐TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle‐ and RGD‐mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD‐l ‐TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.     

Theranostic Prodrug Vesicles for Reactive Oxygen Species‐Triggered Ultrafast Drug Release and Local‐Regional Therapy of Metastatic Triple‐Negative Breast Cancer

A reactive oxygen species (ROS)‐activatable doxorubicin (Dox) prodrug vesicle (RADV) is presented for image‐guided ultrafast drug release and local‐regional therapy of the metastatic triple‐negative breast cancer (TNBC). RADV is prepared by integrating a ROS‐activatable Dox prodrug, a poly(ethylene glycol) (PEG)‐modified photosensitizer pyropheophorbide‐a, an unsaturated phospholipid 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine, and cholesterol into one single nanoplatform. RADV is of extremely high drug loading ratio (27.5 wt%) by self‐assembly of the phospholipid‐mimic Dox prodrug into the liposomal bilayer membrane. RADV displays good colloidal stability to prevent premature drug leakage during the blood circulation and inert photochemotoxicity to avoid nonspecific side effect. RADV passively accumulates at tumor site through the enhanced permeability and retention effect when administrated systemically. Once deposited at the tumor site, RADV generates fluorescent and photoacoustic signals to guide near‐infrared (NIR) laser irradiation, which can induce localized ROS generation, not only to trigger prodrug activation and ultrafast drug release but also conduct photodynamic therapy in a spatiotemporally controlled manner. In combination with NIR laser irradiation, RADV efficiently inhibits the tumor growth and distant metastasis of TNBC. Local‐regional tumor therapy using intelligent theranostic nanomedicine might provide an alternative option for highly efficient treatment of the metastatic TNBC.     

Remote‐Loaded Platelet Vesicles for Disease‐Targeted Delivery of Therapeutics

The recent emergence of biomimetic nanotechnology has facilitated the development of next‐generation nanodelivery systems capable of enhanced biointerfacing. In particular, the direct use of natural cell membranes can enable multivalent targeting functionalities. Herein, this study reports on the remote loading of small molecule therapeutics into cholesterol‐enriched platelet membrane‐derived vesicles for disease‐targeted delivery. Using this approach, high loading yields for two model drugs, doxorubicin and vancomycin, are achieved. Leveraging the surface markers found on platelet membranes, the resultant nanoformulations demonstrate natural affinity toward both breast cancer cells and methicillin‐resistant Staphylococcus aureus. In vivo, this translates to improved disease targeting, increasing the potency of the encapsulated drug payloads compared with free drugs and the corresponding nontargeted nanoformulations. Overall, this work demonstrates that the remote loading of drugs into functional platelet membrane‐derived vesicles is a facile means of fabricating targeted nanoformulations, an approach that can be easily generalized to other cell types in the future.     

Polymer‐Coated Radioluminescent Nanoparticles for Quantitative Imaging of Drug Delivery

Some theranostic nanoparticle (NP) drug delivery systems are capable of measuring drug release rates in situ. This can provide quantitative information regarding drug biodistribution, and drug dose that is delivered to cells or tissues. Here, X‐ray excited optical luminescent (XEOL) NPs coated with poly(glycolide)‐poly(ethylene glycol) (XGP) are used measure the amount of drug released into cells. The photoactive drug protoporphyrin IX (PpIX) is loaded into XGP and is able to attenuate the XEOL NP emission. Measuring an increase in XEOL intensity as PpIX is released enables the measurement of drug release into glioblastoma cells (GBM). Biodistribution studies in a BALB/c mouse GBM intracranial xenograft model show significant XGP accumulation at the site of the GBM xenograft within the brain, and not in adjacent healthy brain tissues. There is no uptake of XGP in the heart or kidneys, the primary organs associated with drug and gadolinium ion toxicity. NP toxicity is tested with U‐138MG GBM in vitro, and NPs show low cytotoxicity at concentrations of 100 μg/mL. In vivo dose escalation studies in BALB/c mice show no adverse effects at doses up to 75 mg/kg. These theranostic NPs offer an approach to quantitatively measure drug release into cells.     

Electrospun Fibrous Architectures for Drug Delivery,Tissue Engineering and Cancer Therapy

The versatile electrospinning technique is recognized as an efficient strategy to deliver active pharmaceutical ingredients and has gained tremendous progress in drug delivery, tissue engineering, cancer therapy, and disease diagnosis. Numerous drug delivery systems fabricated through electrospinning regarding the carrier compositions, drug incorporation techniques, release kinetics, and the subsequent therapeutic efficacy are presented herein. Targeting for distinct applications, the composition of drug carriers vary from natural/synthetic polymers/blends, inorganic materials, and even hybrids. Various drug incorporation approaches through electrospinning are thoroughly discussed with respect to the principles, benefits, and limitations. To meet the various requirements in actual sophisticated in vivo environments and to overcome the limitations of a single carrier system, feasible combinations of multiple drug‐inclusion processes via electrospinning could be employed to achieve programmed, multi‐staged, or stimuli‐triggered release of multiple drugs. The therapeutic efficacy of the designed electrospun drug‐eluting systems is further verified in multiple biomedical applications and is comprehensively overviewed, demonstrating promising potential to address a variety of clinical challenges.     

Biodegradable Hydrophobic Injectable Polymers for Drug Delivery and Regenerative Medicine

Biodegradable, hydrophobic, and injectable liquid polymers are capable of achieving the minimally invasive, sustained, and local release of drugs. These hydrophobic injectable polymers also have potential in the area of regenerative medicine where the biomaterial should be stable for a certain period and then degrade to allow the growth of cells/tissues. This review presents exclusive coverage of biocompatible hydrophobic injectable pasty or liquid polymers that can be injected without the use of any solvent for drug delivery, tissue augmentation, and regenerative medicine application. The synthesis methodologies of several major types of hydrophobic pasty polymers used in the biomedical fields and their properties with the foremost criteria to serve as injectable biomaterial for localized drug delivery and regenerative medicine is described. The hydrophobic biodegradable injectable polymers discussed are aliphatic polyesters, polycarbonates and polyanhydrides, prepared from: lactic acid, glycolic acid, caprolactone, aliphatic diols and diacids, hydroxy fatty acids, and triglycerides such as castor oil.     

A Facile Magnetic Extrusion Method for Preparing Endosome-Derived Vesicles for Cancer Drug Delivery

To date, the scaled-up manufacturing and efficient drug loading of exosomes are two existing challenges limiting the clinical translation of exosome-based drug delivery. Herein, a facile magnetic extrusion method is developed for preparing endosome-derived vesicles, also known as exosome mimetics (EMs), which share the same biological origin and similar morphology, composition, and biofunctions with native exosomes. The high yield and consistency of this magnetic extrusion method help to overcome the manufacturing bottleneck in exosome research. Moreover, the proposed standardized multi-step method readily facilitates the ammonium sulfate gradient approach to actively load chemodrugs such as doxorubicin into EMs. The engineered EMs developed and tested here exhibit comparable drug delivery properties as do native exosomes, and potently inhibit tumor growth by delivering doxorubicin in an orthotopic breast tumor model. These findings demonstrate that EMs can be prepared in a facile and scaled-up manner as a promising biological nanomedicine for cancer drug delivery.     

Amplification of Cerenkov Luminescence Using Semiconducting Polymers for Cancer Theranostics

The therapeutic efficacy of photodynamic therapy is limited by the ability of light to penetrate tissues. Due to this limitation, Cerenkov luminescence (CL) from radionuclides has recently been proposed as an alternative light source in a strategy referred to as Cerenkov radiation-induced therapy (CRIT). Semiconducting polymer nanoparticles (SPNs) have ideal optical properties, such as large absorption cross-sections and broad absorbance, which can be utilized to harness the relatively weak CL produced by radionuclides. SPNs can be doped with photosensitizers and have ≈100% energy transfer efficiency by multiple energy transfer mechanisms. Herein, an optimized photosensitizer-doped SPN is investigated as a nanosystem to harness and amplify CL for cancer theranostics. It is found that semiconducting polymers significantly amplify CL energy transfer efficiency. Bimodal positron emission tomography (PET) and optical imaging studies show high tumor uptake and retention of the optimized SPNs when administered intravenously or intratumorally. Lastly, it is found that photosensitizer-doped SPNs have excellent potential as a cancer theranostics nanosystem in an in vivo tumor therapy study. This study shows that SPNs are ideally suited to harness and amplify CL for cancer theranostics, which may provide a significant advancement for CRIT that are unabated by tissue penetration limits.     

Zwitterionic Polysulfamide Drug Nanogels with Microwave Augmented Tumor Accumulation and On‐Demand Drug Release for Enhanced Cancer Therapy

Zwitterionic polymers demonstrate as a class of antifouling materials with long blood circulation in living subjects. Despite extensive research on their antifouling abilities, the responsive zwitterionic polymers that can change their properties by mild outside signals are poorly explored. Herein, a sulfamide‐based zwitterionic monomer is developed and used to synthesize a series of polysulfamide‐based (poly (2‐((2‐(methacryloyloxy)ethyl) dimethylammonio)acetyl) (phenylsulfonyl) amide (PMEDAPA)) nanogels as drug carriers for effective cancer therapy. PMEDAPA nanogels are proved to exhibit prolonged blood circulation without inducing the accelerated blood clearance phenomenon. Intriguingly, PMEDAPA nanogels can sensitively respond to hyperthermia by adjusting the crosslinker degree. After modified with transferrin (Tf), the nanogels (PMEDAPA‐Tf) achieve shielded tumor targeting at normothermia, while exhibiting recovered tumor targeting at hyperthermia, leading to enhanced tumor accumulation. Meanwhile, PMEDAPA‐Tf nanogels show superior penetration ability in 3D tumor spheroids and faster drug release at hyperthermia compared with that at normothermia. In combination with mild microwave heating (≈41 °C), the drug‐loaded PMEDAPA‐Tf nanogels show a pronounced tumor inhibition effect in a humanized orthotropic liver cancer model. Therefore, the study provides a novel hyperthermia‐responsive zwitterionic nanogel that can achieve augmented tumor accumulation and on‐demand drug release assisted with clinically used microwave heating for cancer therapy.     

Camouflaged Hybrid Cancer Cell-Platelet Fusion Membrane Nanovesicles Deliver Therapeutic MicroRNAs to Presensitize Triple-Negative Breast Cancer to Doxorubicin

Camouflaged cell-membrane-based nanoparticles have gained increasing attention owing to their improved biocompatibility and immunomodulatory properties. Using nanoparticles prepared from the membranes of specific cell types or fusions derived from different cells membranes, their functional performance could be improved in several aspects. Here, cell membranes extracted from breast cancer cells and platelets are used to fabricate a hybrid-membrane vesicle (cancer cell-platelet-fusion-membrane vesicle, CPMV) loaded with therapeutic microRNAs (miRNAs) for the treatment of triple-negative breast cancer (TNBC). A clinically scalable microfluidic platform is presented for fusion of cell membranes. The reconstitution process during synthesis allows for efficient loading of miRNAs into CPMVs. Conditions for preparation of miRNA-loaded CPMVs are systematically optimized and their property of homing to source cells is demonstrated using in vitro experiments and therapeutic evaluation in vivo. In vitro, the CPMVs exhibit significant recognition of their source cells and avoided engulfment by macrophages. After systemic delivery in mice, CPMVs show a prolonged circulation time and site-specific accumulation at implanted TNBC-xenografts. The delivered antimiRNAs are sensitized TNBCs to doxorubicin, resulting in an improved therapeutic response and survival rate. This strategy has considerable potential for clinical translation to improve personalized therapy for breast cancer and other malignancies.     

Bioengineered Biomimetic and Bioinspired Noninvasive Drug Delivery Systems

The main purpose herein is to provide an up-to-date review on noninvasive biomimetic, bioinspired, and bioengineered drug delivery system (DDS). Noninvasive DDS is an ever-growing field critical for the applicability of drugs. It offers noninvasive administration routes with improved controlled, targeted, and triggered drug delivery. Noninvasive DDS employ many approaches and strategies, such as, nano- and microparticles, lipid-based systems, sonophoresis, electrophoresis and iontophoresis, penetration enhancers, microneedles, and gels. The last decade seen a surge in research papers employing the paradigms of biomimicry, bioinspiration, and bioengineering. However, since the use of these terms in noninvasive DDS field is often inconsistent and unclear, some generalized perspectives are provided on the possible usage of these terms in future publications. Additionally, a critical discussion on the novelty and origins of these paradigms is provided. The advantages and disadvantages of each of the noninvasive routes and their current main limitations are summarized. The main aspects of indicated fields are discussed: The unique physiology of the related tissues, the main hurdles for mass transport, the various DDS tested, and materials selection. Finally, the basic concepts and therapeutic effects of these DDS are discussed and future venues for noninvasive biomimetic, bioinspired, and bioengineered DDS research are proposed.     

Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy

Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.     

Cell-Based Delivery Systems: Emerging Carriers for Immunotherapy

Immunotherapy is leading a paradigm shift in the treatment of various diseases, including tumors, auto-immune diseases, and infectious diseases. However, the limited response rate and systemic side effects significantly impede the clinical applications of immunotherapy. As natural carriers for proteins and molecules, cells with low immunogenicity and toxicity have attracted considerable attention for biomedical applications and have achieved encouraging progress especially in immunotherapy. The convergence of multiple disciplines has equipped cell-based delivery systems with control over their spatiotemporal distribution to enhance treatment efficacy and reduce side effects. Here, an overview of the fundamentals and design principles of cell-based delivery systems followed by a perspective that includes the most recent advances of various cells as delivery carriers, with a special focus on the implications of cell-based delivery systems for immunotherapy is offered.     

Recent Advances in Nanomodulators for Augmenting Cancer Immunotherapy in Cold Tumors: Insights from Drug Delivery to Drug-Free Strategies

Immunotherapy has significantly improved cancer treatment, yet the immunosuppressive tumor microenvironment (TME) remains a substantial impediment to therapeutic efficacy. Nanomodulators have emerged as promising tools to address immunosuppressive factors within the TME, enhancing clinical interventions such as immunotherapy, chemotherapy, and radiotherapy while minimizing associated safety risks with immune modulators. In this review, recent advancements are spotlighted in TME-targeted nanomodulators from drug delivery to drug-free concepts. First, nanomodulators designed to synergize with various immunomodulatory agents, including gene tools (mRNA, siRNA, miRNA, plasmid DNA, and CRISPER system), cytokines, immune agonists, and inhibitors are analyzed. Subsequently, recently developed drug-free nanomodulators designed to modulate the physicochemical and biological properties in the microenvironment of solid tumors are succinctly presented. Finally, integrative perspectives on the future development and challenges of nanomodulators in assisting cancer immunotherapy are offered as conclusions.     

Graphene Oxide Based Fluorescent DNA Aptasensor for Liver Cancer Diagnosis and Therapy

Graphene oxide (GO)-based fluorescent DNA aptasensors are promising nanomaterials in bioassays owing to the fluorescent ultrasensitivity and target identification ability. However, their in vivo application remains an appealing yet significantly challenging task. In this contribution, for the first time, a nanomaterial for in vivo diagnosis and therapy of liver tumors is demonstrated. A DNA nanomaterial consisting of DNA tetrahedron and aptamers, aggregation-induced emission luminogens, and antitumor drug doxorubicin, is fabricated and attached on the GO surface. This developed hybrid with good biocompatibility exhibits high selectivity to target liver cancer cells, and performs well in in vitro and in vivo liver tumor fluorescence imaging diagnosis and chemotherapy. Additionally, a GO-based fluorescent DNA nanodevice is also constructed by using microfluidic chips for liver tumor cell screening.