bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒10‒10
twenty papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Rev Mater. 2021 Sep 28. 1-22
      Vaccines are the key technology to combat existing and emerging infectious diseases. However, increasing the potency, quality and durability of the vaccine response remains a challenge. As our knowledge of the immune system deepens, it becomes clear that vaccine components must be in the right place at the right time to orchestrate a potent and durable response. Material platforms, such as nanoparticles, hydrogels and microneedles, can be engineered to spatially and temporally control the interactions of vaccine components with immune cells. Materials-based vaccination strategies can augment the immune response by improving innate immune cell activation, creating local inflammatory niches, targeting lymph node delivery and controlling the time frame of vaccine delivery, with the goal of inducing enhanced memory immunity to protect against future infections. In this Review, we highlight the biological mechanisms underlying strong humoral and cell-mediated immune responses and explore materials design strategies to manipulate and control these mechanisms.
    Keywords:  Biomaterials - vaccines; Biomedical engineering; Chemical engineering; Vaccines
  2. Adv Mater. 2021 Oct 03. e2105711
      Gene therapy has shown great potential for neurodegenerative diseases with complex pathology. However, its therapeutic effect is limited due to the delivery barriers and its own single function. Herein, self-catalytic small interfering RNA (siRNA) nanocarriers (S/Ce-PABMS) are developed to catalyze delivery process and treatment process for synergistic treatment of neurodegenerative diseases. On the one hand, the rough surface of S/Ce-PABMS mediated by ceria (CeO2 ) nanozymes can catalyze cellular uptake in the delivery process, so that S/Ce-PABMS with acetylcholine analogs penetrate the blood-brain barrier and enter neurons more effectively. On the other hand, CeO2 nanozymes can catalyze the treatment process by scavenging excess reactive oxygen species, and cooperate with siRNA targeting SNCA to decrease the α-synuclein (α-syn) aggregation and alleviate the parkinsonian pathology. Moreover, the S/Ce-PABMS treatment reduces the number of activated microglia and regulates the release of inflammatory cytokine, thereby relieving neuroinflammation. After treatment with S/Ce-PABMS, dyskinesia in Parkinson's disease model mice has been significantly alleviated. The finding shows that the self-catalytic nanocarriers S/Ce-PABMS have great potential in the treatment of neurodegenerative diseases. This article is protected by copyright. All rights reserved.
    Keywords:  brain delivery; nanozymes; neurodegenerative diseases; self-catalytic; siRNA; synergistic treatment
  3. Nat Commun. 2021 Oct 07. 12(1): 5871
      Optogenetics combined with electrical recording has emerged as a powerful tool for investigating causal relationships between neural circuit activity and function. However, the size of optogenetically manipulated tissue is typically 1-2 orders of magnitude larger than that can be electrically recorded, rendering difficulty for assigning functional roles of recorded neurons. Here we report a viral vector-delivery optrode (VVD-optrode) system for precise integration of optogenetics and electrophysiology in the brain. Our system consists of flexible microelectrode filaments and fiber optics that are simultaneously self-assembled in a nanoliter-scale, viral vector-delivery polymer carrier. The highly localized delivery and neuronal expression of opsin genes at microelectrode-tissue interfaces ensure high spatial congruence between optogenetically manipulated and electrically recorded neuronal populations. We demonstrate that this multifunctional system is capable of optogenetic manipulation and electrical recording of spatially defined neuronal populations for three months, allowing precise and long-term studies of neural circuit functions.
  4. Anal Chem. 2021 Oct 08.
      The development of multifunctional nanoplatforms that integrate both diagnostic and therapeutic functions has always been extremely desirable and challenging in the cancer combat. Here, we report an endogenous miRNA-activated DNA nanomachine (EMDN) in living cells for concurrent sensitive miRNA imaging and activatable gene silencing. EMDN is constructed by interval hybridization of two functional DNA monomers (R/HP and F) to a DNA nanowire generated by hybridization chain reaction. After the target cell-specific transportation of EMDN, intracellular let-7a miRNA initiates the DNA nanomachine by DNA strand displacement cascades, resulting in an amplified fluorescence resonance energy-transfer signal and the release of many free HP sequences. The restoration of HP hairpin structures further activates the split-DNAzyme to identify and cleave the EGR-1 mRNA to realize gene silencing therapy. The proposed EMDN shows efficient cell internalization, good biological stability, rapid reaction kinetics, and the ability to avoid false-positive signals, thus ensuring reliable miRNA imaging in living cells. Meanwhile, the controlled activation of the split-DNAzyme activity regulated by the intracellular specific miRNA may be promising in the precise treatment of cancer. Collectively, this strategy provides a valuable nanoplatform for early clinical diagnosis and activatable gene therapy of tumors.
  5. Adv Sci (Weinh). 2021 Oct 07. e2102741
      Supramolecular self-assemblies of dendritic peptides with well-organized nanostructures have great potential as multifunctional biomaterials, yet the complex self-assembly mechanism hampers their wide exploration. Herein, a self-stabilized supramolecular assembly (SSA) constructed from a PEGylated dendritic peptide conjugate (PEG-dendritic peptide-pyropheophorbide a, PDPP), for augmenting tumor retention and therapy, is reported. The supramolecular self-assembly process of PDPP is concentration-dependent with multiple morphologies. By tailoring the concentration of PDPP, the supramolecular self-assembly is driven by noncovalent interactions to form a variety of SSAs (unimolecular micelles, oligomeric aggregates, and multi-aggregates) with different sizes from nanometer to micrometer. SSAs at 100 nm with a spherical shape possess extremely high stability to prolong blood circulation about 4.8-fold higher than pyropheophorbide a (Ppa), and enhance tumor retention about eight-fold higher than Ppa on day 5 after injection, which leads to greatly boosting the in vivo photodynamic therapeutic efficiency. RNA-seq demonstrates that these effects of SSAs are related to the inhibition of MET-PI3K-Akt pathway. Overall, the supramolecular self-assembly mechanism for the synthetic PEGylated dendritic peptide conjugate sheds new light on the development of supramolecular assemblies for tumor therapy.
    Keywords:  colloidal stability; dendritic peptides; dissipative particle dynamics simulations; polymeric conjugates; supramolecular assembly; transcriptome analysis; tumor retention and therapy
  6. J Control Release. 2021 Oct 01. pii: S0168-3659(21)00526-5. [Epub ahead of print]
      Mutations in rhodopsin lead to its misfolding resulting in autosomal dominant retinitis pigmentosa (adRP). Pharmacological inhibition of the ATP-driven chaperone valosin-containing protein (VCP), a molecular checkpoint for protein quality control, slows down retinal degeneration in animal models. However, poor water-solubility of VCP inhibitors poses a challenge to their clinical translation as intravitreal injections for retinal treatment. In order to enable the delivery of VCP inhibitors, we have developed and investigated two formulations for the VCP inhibitor ML240. Nanoformulations of ML240 were obtained by using amphiphilic polymers methoxy-poly (ethylene glycol)5kDa-cholane (mPEG5kDa-cholane) and methoxy-poly (ethylene glycol)5kDa-cholesterol (mPEG5kDa-cholesterol). Both formulations increased the water-solubility of ML240 by two orders of magnitude and prolonged the drug released over ten days. In addition, encapsulation of ML240 in mPEG5kDa-cholane showed superior photoreceptor protection at lower drug concentrations, normalized rhodopsin localization, and alleviated inflammatory microglial responses in an ex vivo rat model of retinal degeneration. The study demonstrates the potential of VCP inhibitor nanoformulations to treat adRP, a pharmacologically orphan disease.
    Keywords:  Drug delivery; Intravitreal injection; Retinal degeneration; Self-assembling polymers; VCP inhibitor
  7. Nat Biomed Eng. 2021 Sep;5(9): 983-997
      Oral formulations of insulin are typically designed to improve its intestinal absorption and increase its blood bioavailability. Here we show that polymerized ursodeoxycholic acid, selected from a panel of bile-acid polymers and formulated into nanoparticles for the oral delivery of insulin, restored blood-glucose levels in mice and pigs with established type 1 diabetes. The nanoparticles functioned as a protective insulin carrier and as a high-avidity bile-acid-receptor agonist, increased the intestinal absorption of insulin, polarized intestinal macrophages towards the M2 phenotype, and preferentially accumulated in the pancreas of the mice, binding to the islet-cell bile-acid membrane receptor TGR5 with high avidity and activating the secretion of glucagon-like peptide and of endogenous insulin. In the mice, the nanoparticles also reversed inflammation, restored metabolic functions and extended animal survival. When encapsulating rapamycin, they delayed the onset of diabetes in mice with chemically induced pancreatic inflammation. The metabolic and immunomodulatory functions of ingestible bile-acid-polymer nanocarriers may offer translational opportunities for the prevention and treatment of type 1 diabetes.
  8. Small. 2021 Oct 04. e2104831
      Programmable engineered DNA origami provides infinite possibilities for customizing nanostructures with controllable precision and configurable functionality. Here, a strategy for fabricating an amphiphilic triangular DNA origami with a central nanopore that integrates phase-stabilizing, porous-gated, and affinity-delivering effects is presented. By introducing the DNA origami as a single-component surfactant, the water-in-oil-in-water (W/O/W) emulsion is effectively stabilized with decreased interfacial tension. Microscopic observation validates the attachment of the DNA origami onto the water-in-oil and oil-in-water interfaces. Furthermore, fluorescence studies and molecular docking simulations indicate the binding interactions of DNA origami with arbutin and coumaric acid at docking sites within central nanopores. These central nanopores are functionalized as molecular gates and affinity-based scaffold for the zero-order release of arbutin and coumaric acid at a constant rate regardless of concentration gradient throughout the whole releasing period. In vivo zebrafish results illustrate the advantages of this zero-order release for anti-melanogenesis therapy over direct exposure or Fickian diffusion. The DNA origami-based W/O/W emulsion presents anti-melanogenic effects against UV-B exposure without cardiotoxicity or motor toxicity. These results demonstrate that this non-toxic amphiphilic triangular DNA origami is capable of solely stabilizing the W/O/W emulsion as well as serving as nanopore gates and affinity-based scaffold for constant release.
    Keywords:  DNA nanotechnology; affinity scaffold; double emulsion; whitening efficacy; zero-order release
  9. Adv Mater. 2021 Oct 07. e2106606
      Glioblastoma (GBM) is the most common and aggressive primary brain tumor, and it is associated with poor prognosis because of invasive growth. To date, surgery followed by chemotherapy and radiotherapy remains the standard treatment strategy for GBM after the exact location of the tumor has been confirmed. However, challenges still exist for many GBM patients when surgery is difficult or impossible; in many cases, surgery cannot remove the tumor completely, because the tumor tends to spread into surrounding tissues. Herein, we report the design, fabrication and application of a heterogenous silk fibroin microneedle (SMN) patch for circumventing the blood-brain barrier and releasing multiple drugs directly to the tumor site for drug combination treatment. The biocompatible and biodegradable SMN patch can dissolve slowly over time, allowing the sustained release of multiple drugs at different concentrations over an extended period of time. Furthermore, it can be triggered remotely to induce rapid drug delivery at a designated stage after implantation. In the GBM mouse models with and without tumor resection in distinct cell lines, two clinically relevant chemotherapeutic agents(thrombin and temozolomide)and targeted drug (bevacizumab) were loaded into the SMN patch at different doses and with individually controlled release profiles. The drugs were spatiotemporally and sequentially delivered to the tumor site in the mouse brain during the dissolution of the SMN patch and maintained at levels above those effective for hemostasis, anti-angiogenesis and apoptosis of tumor cells. Device application was non-toxic and resulted in both decreased tumor volume and increased survival rate in mice. The SMN patch with on-demand multi-drug delivery has potential applications for the combined administration of multiple therapeutic drugs for the clinical treatment of brain tumors when other methods are insufficient. This article is protected by copyright. All rights reserved.
    Keywords:  Drug Delivery; glioblastoma; microneedle patch; silk protein
  10. Nanoscale. 2021 Oct 08.
      Nanoparticle-sensitized photoporation for intracellular delivery of external compounds usually relies on the use of spherical gold nanoparticles as sensitizing nanoparticles. As they need stimulation with visible laser light, they are less suited for transfection of cells in thick biological tissues. In this work, we have explored black phosphorus quantum dots (BPQDs) as alternative sensitizing nanoparticles for photoporation with a broad and uniform absorption spectrum from the visible to the near infra-red (NIR) range. We demonstrate that BPQD sensitized photoporation allows efficient intracellular delivery of both siRNA (>80%) and mRNA (>40%) in adherent cells as well as in suspension cells. Cell viability remained high (>80%) irrespective of whether irradiation was performed with visible (532 nm) or near infrared (800 nm) pulsed laser light. Finally, as a proof of concept, we used BPQD sensitized photoporation to deliver macromolecules in cells with thick phantom tissue in the optical path. NIR laser irradiation resulted in only 1.3× reduction in delivery efficiency as compared to photoporation without the phantom gel, while with visible laser light the delivery efficiency was reduced 2×.
  11. Adv Mater. 2021 Oct 03. e2105136
      The physiological chirality of extracellular environments is substantially affected by pathological diseases. However, how this stereochemical variation drives host immunity remains poorly understood. Here, we report that pathology-mimetic M-nanofibrils-but not physiology-mimetic P-nanofibrils-act as a defense mechanism that helps to restore tissue homeostasis by manipulating immunological response. Quantitative multi-omics in vivo and in vitro showed that M-nanofibrils significantly inhibited inflammation and promoted tissue regeneration by upregulating M2 macrophage polarization and downstream immune signaling compared with P-nanofibrils. Molecular analysis and theoretical simulation demonstrated that M-chirality displayed higher stereo-affinity to cellular binding, which induced higher cellular contractile stress and activated mechanosensitive ion channel PIEZOl to conduct Ca2+ influx. In turn, the nuclear transfer of STAT was biased by Ca2+ influx to promote M2 polarization. These findings underscore the structural mechanisms of disease, providing design basis for immunotherapy with bionic functional materials. This article is protected by copyright. All rights reserved.
    Keywords:  chirality nanofibrils; immunological response; macrophage polarization
  12. Adv Mater. 2021 Oct 07. e2105670
      Ischemia-reperfusion injury (IRI) remains as a critical challenge for organ transplantation. We report herein an enzyme therapeutic based on superoxide dismutase and catalase for effective mitigation of IRI and pathogen-induced liver injury, affording provides a therapeutic for organ transplantation and other diseases. This article is protected by copyright. All rights reserved.
    Keywords:  antioxidant; enzyme therapeutic; ischemia-reperfusion injury; organ transplantation; reactive oxygen species
  13. Adv Healthc Mater. 2021 Oct 03. e2101407
      Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.
    Keywords:  cancer therapy; colloidal stability; nanorods; prodrug self-assembly; zwitterions
  14. Nucleic Acids Res. 2021 Oct 06. pii: gkab888. [Epub ahead of print]
      Liposomes are widely used as synthetic analogues of cell membranes and for drug delivery. Lipid-binding DNA nanostructures can modify the shape, porosity and reactivity of liposomes, mediated by cholesterol modifications. DNA nanostructures can also be designed to switch conformations by DNA strand displacement. However, the optimal conditions to facilitate stable, high-yield DNA-lipid binding while allowing controlled switching by strand displacement are not known. Here, we characterized the effect of cholesterol arrangement, DNA structure, buffer and lipid composition on DNA-lipid binding and strand displacement. We observed that binding was inhibited below pH 4, and above 200 mM NaCl or 40 mM MgCl2, was independent of lipid type, and increased with membrane cholesterol content. For simple motifs, binding yield was slightly higher for double-stranded DNA than single-stranded DNA. For larger DNA origami tiles, four to eight cholesterol modifications were optimal, while edge positions and longer spacers increased yield of lipid binding. Strand displacement achieved controlled removal of DNA tiles from membranes, but was inhibited by overhang domains, which are used to prevent cholesterol aggregation. These findings provide design guidelines for integrating strand displacement switching with lipid-binding DNA nanostructures. This paves the way for achieving dynamic control of membrane morphology, enabling broader applications in nanomedicine and biophysics.
  15. Adv Mater. 2021 Oct 04. e2105667
      The wet and highly dynamic environment of the mouth makes local treatment of oral mucosal diseases challenging. To overcome this, a photo-crosslinking hydrogel adhesive is developed inspired by the success of light-curing techniques in dentistry. The adhesive operates on a fast (within 5 s) phototriggered S-nitrosylation coupling reaction and employs imine anchoring to connect to host tissues. Unlike other often-used clinical agents that adhere weakly and for short durations, this thin, elastic, adhesive, and degradable cyclic o-nitrobenzyl-modified hyaluronic acid gel protects mucosal wounds from disturbance by liquid rinsing, oral movement, and friction for more than 24 h. The results from both rat and pig oral mucosa repair models demonstrate that this new gel adhesive creates a favorable microenvironment for tissue repair and can shorten tissue healing time. This study thus illustrates a therapeutic strategy with the potential to advance the treatment of oral mucosal defects in the clinic.
    Keywords:  hydrogels; o-nitrobenzyl photocages; oral mucosal diseases; photo-crosslinking; tissue adhesives
  16. ACS Nano. 2021 Oct 04.
      Stroke is a primary cause of death and disability worldwide, while effective and safe drugs remain to be developed for its clinical treatment. Herein, we report bioactive nanoparticle-derived multifunctional nanotherapies for ischemic stroke, which are engineered from a pharmacologically active oligosaccharide material (termed as TPCD) prepared by covalently conjugating a radical-scavenging compound (Tempol) and a hydrogen-peroxide-eliminating moiety of phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin. Of note, combined functional moieties of Tempol and PBAP on β-cyclodextrin contribute to antioxidative and anti-inflammatory activities of TPCD. Cellularly, TPCD nanoparticles (i.e., TPCD NPs) reduced oxygen-glucose deprivation-induced overproduction of oxidative mediators, increased antioxidant enzyme expression, and suppressed microglial-mediated inflammation, thereby inhibiting neuronal apoptosis. After intravenous (i.v.) delivery, TPCD NPs could efficiently accumulate at the cerebral ischemic injury site of mice with middle cerebral artery occlusion (MCAO), showing considerable distribution in cells relevant to the pathogenesis of stroke. Therapeutically, TPCD NPs significantly decreased infarct volume and accelerated recovery of neurological function in MCAO mice. Mechanistically, efficacy of TPCD NPs is achieved by its antioxidative, anti-inflammatory, and antiapoptotic effects. Furthermore, TPCD NPs can function as a reactive oxygen species labile nanovehicle to efficiently load and triggerably release an inflammation-resolving peptide Ac2-26, giving rise to an inflammation-resolving nanotherapy (i.e., ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced in vivo efficacies, largely resulting from its additional inflammation-resolving activity. Consequently, TPCD NP-derived nanomedicines can be further developed as promising targeted therapies for stroke and other inflammation-associated cerebrovascular diseases.
    Keywords:  anti-inflammation; antioxidative stress; bioactive nanoparticle; ischemic stroke; nanotherapy
  17. J Control Release. 2021 Oct 01. pii: S0168-3659(21)00528-9. [Epub ahead of print]
      Starvation therapy based on glucose oxidase (GOx) has attracted considerable attention in tumor treatment. However, several shortcomings severely hinder its further applications, including limited therapeutic efficacy, poor enzyme stability, and potential side effects. Herein, a strategy of cascade reaction-enhanced combined therapy based on the oxygen-evolving multifunctional nanoreactors is proposed for tumor therapy. The GOx and catalase (CAT) are immobilized in metal-organic frameworks by biomimetic mineralization to improve their stability via spatial confinement. The GOx can consume glucose, reduce ATP levels, and down-regulate the expression of heat shock proteins, which consequently sensitize tumor cells to indocyanine green-based photothermal therapy. Furthermore, the hydrogen peroxide generated by GOx as well as overexpressed in tumor can be decomposed by CAT and continuously generate oxygen, which further enhance the efficacy of oxygen-dependent starvation therapy and photodynamic therapy. The nanoreactors are directly delivered to the superficial tumor by microneedles, achieving efficient tumor accumulation and dramatically strengthened antitumor efficacy without obvious side effects, which provides a valuable paradigm for the application of cascade reaction-based combined therapy.
    Keywords:  Cancer therapy; Cascade reaction; Glucose oxidase; Microneedles; Oxygen supply
  18. Nat Biomed Eng. 2021 Sep;5(9): 1059-1068
      Lipid nanoparticles (LNPs) for the efficient delivery of drugs need to be designed for the particular administration route and type of drug. Here we report the design of LNPs for the efficient delivery of therapeutic RNAs to the lung via nebulization. We optimized the composition, molar ratios and structure of LNPs made of lipids, neutral or cationic helper lipids and poly(ethylene glycol) (PEG) by evaluating the performance of LNPs belonging to six clusters occupying extremes in chemical space, and then pooling the lead clusters and expanding their diversity. We found that a low (high) molar ratio of PEG improves the performance of LNPs with neutral (cationic) helper lipids, an identified and optimal LNP for low-dose messenger RNA delivery. Nebulized delivery of an mRNA encoding a broadly neutralizing antibody targeting haemagglutinin via the optimized LNP protected mice from a lethal challenge of the H1N1 subtype of influenza A virus, and delivered mRNA more efficiently than LNPs previously optimized for systemic delivery. A cluster approach to LNP design may facilitate the optimization of LNPs for other administration routes and therapeutics.
  19. Adv Sci (Weinh). 2021 Oct 04. e2101176
      Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.
    Keywords:  advanced breast cancer; drug screening; patient-derived organoids; personalized therapy
  20. Adv Mater. 2021 Oct 05. e2101572
      Though numerous external-stimuli-triggered tumor therapies, including phototherapy, radiotherapy, and sonodynamic therapy have made great progress in cancer therapy, the low penetration depth of the laser, safety concerns of radiation, the therapeutic resistance, and the spatio-temporal constraints of the specific equipment restrict their convenient clinical applications. What is more, the inherent physiological barriers of the tumor microenvironment (TME), including hypoxia, heterogeneity, and high expression of antioxidant molecules also restrict the efficiency of tumor therapy. As a result, the development of nanoplatforms responsive to endogenous stimuli (such as glucose, acidic pH, cellular redox events, and etc.) has attracted great attention for starvation therapy, ion therapy, prodrug-mediated chemotherapy, or enzyme-catalyzed therapy. In addition, nanomedicines can be modified by some targeted units for precisely locating in subcellular organelles and boosting the destroying of tumor tissue, decreasing the dosage of nanoagents, reducing side effects, and enhancing the therapeutic efficiency. Herein, the properties of the TME, the advantages of endogenous stimuli, and the principles of subcellular-organelle-targeted strategies will be emphasized. Some necessary considerations for the exploitation of precision medicine and clinical translation of multifunctional nanomedicines in the future are also pointed out.
    Keywords:  cancer therapy; endogenous stimuli; nanomedicine; precise therapy; subcellular organelles; targeting