Corrosion‐Activated Chemotherapeutic Function of Nanoparticulate Platinum as a Cisplatin Resistance‐Overcoming Prodrug with Limited Autophagy Induction

Despite nanoparticulate platinum (nano‐Pt) has been validated to be acting as a platinum‐based prodrug for anticancer therapy, the key factor in controlling its cytotoxicity remains to be clarified. In this study, it is found that the corrosion susceptibility of nano‐Pt can be triggered by inducing the oxidization of superficial Pt atoms, which can kill both cisplatin‐sensitive/resistance cancer cells. Direct evidence in the oxidization of superficial Pt atoms is validated to observe the formation of platinum oxides by X‐ray absorption spectroscopy. The cytotoxicity is originated from the dissolution of nano‐Pt followed by the release of highly toxic Pt ions during the corrosion process. Additionally, the limiting autophagy induction by nano‐Pt might prevent cancer cells from acquiring autophagy‐related drug resistance. With such advantages, the possibility of further autophagy‐related drug resistance could be substantially reduced or even eliminated in cancer cells treated with nano‐Pt. Moreover, nano‐Pt is demonstrated to kill cisplatin‐resistant cancer cells not only by inducing apoptosis but also by inducing necrosis for pro‐inflammatory/inflammatory responses. Thus, nano‐Pt treatment might bring additional therapeutic benefits by regulating immunological responses in tumor microenvironment. These findings support the idea that utilizing nano‐Pt for its cytotoxic effects might potentially benefit patients with cisplatin resistance in clinical chemotherapy.     

Antibody Conjugated PLGA Nanoparticles for Targeted Delivery of Paclitaxel Palmitate: Efficacy and Biofate in a Lung Cancer Mouse Model

Aberrant signaling of the epidermal growth factor receptor (EGFR) is common to a variety of human cancers and is also found to be over‐expressed in most cases of non‐small cell lung cancer. For the development of a molecularly targeted therapy, cetuximab‐conjugated nanoparticles (immunonanoparticles, INPs) are designed and loaded with the lipophilic paclitaxel palmitate (pcpl) prodrug. Oleyl cysteineamide (OCA) is synthesized whereby its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs, facilitating bioconjugation to cetuximab by thioether bonds. It is demonstrated that the in vitro targeting efficiency and improved cellular internalization and cytotoxicity of this targeted delivery system in lung cancer cells over‐expressing EGFR. A quantitative measure of the high binding affinity of INPs to EGFR is demonstrated using surface plasmon resonance. In vivo tolerability and enhanced efficacy of cetuximab pcpl INPs in a metastatic lung cancer model are reported. Its therapeutic efficacy in A549‐luc‐C8 lung tumors is shown using non‐invasive bioluminescent imaging. Intravenous administration of cetuximab pcpl INPs to mice results in significantly higher inhibition of tumor growth and increased survival rates as compared to the non‐targeted drug solution, drug‐loaded nanoparticles or blank INPs. Pharmacokinetics and organ biodistribution of the prodrug and parent drug are evaluated by LC‐MS/MS in lung tumor bearing mice. No enhanced total accumulation of nanoparticles or INPs is found at the tumor tissue. However, persistent pcpl levels with sustained conversion and release of paclitaxel are observed for the encapsulated prodrug possibly suggesting the formation of a drug reservoir. The overall results indicate the potential of this promising targeted platform for the improved treatment of lung cancer and other EGFR positive tumors.     

Daunorubicin‐Loaded DNA Origami Nanostructures Circumvent Drug‐Resistance Mechanisms in a Leukemia Model

Many cancers show primary or acquired drug resistance due to the overexpression of efflux pumps. A novel mechanism to circumvent this is to integrate drugs, such as anthracycline antibiotics, with nanoparticle delivery vehicles that can bypass intrinsic tumor drug‐resistance mechanisms. DNA nanoparticles serve as an efficient binding platform for intercalating drugs (e.g., anthracyclines doxorubicin and daunorubicin, which are widely used to treat acute leukemias) and enable precise structure design and chemical modifications, for example, for incorporating targeting capabilities. Here, DNA nanostructures are utilized to circumvent daunorubicin drug resistance at clinically relevant doses in a leukemia cell line model. The fabrication of a rod‐like DNA origami drug carrier is reported that can be controllably loaded with daunorubicin. It is further directly verified that nanostructure‐mediated daunorubicin delivery leads to increased drug entry and retention in cells relative to free daunorubicin at equal concentrations, which yields significantly enhanced drug efficacy. Our results indicate that DNA origami nanostructures can circumvent efflux‐pump‐mediated drug resistance in leukemia cells at clinically relevant drug concentrations and provide a robust DNA nanostructure design that could be implemented in a wide range of cellular applications due to its remarkably fast self‐assembly (≈5 min) and excellent stability in cell culture conditions.     

pH‐ and NIR Light‐Responsive Polymeric Prodrug Micelles for Hyperthermia‐Assisted Site‐Specific Chemotherapy to Reverse Drug Resistance in Cancer Treatment

Despite the exciting advances in cancer chemotherapy over past decades, drug resistance in cancer treatment remains one of the primary reasons for therapeutic failure. IR‐780 loaded pH‐responsive polymeric prodrug micelles with near infrared (NIR) photothermal effect are developed to circumvent the drug resistance in cancer treatment. The polymeric prodrug micelles are stable in physiological environment, while exhibit fast doxorubicin (DOX) release in acidic condition and significant temperature elevation under NIR laser irradiation. Phosphorylcholine‐based biomimetic micellar shell and acid‐sensitive drug conjugation endow them with prolonged circulation time and reduced premature drug release during circulation to conduct tumor site‐specific chemotherapy. The polymeric prodrug micelles combined with NIR laser irradiation could significantly enhance intracellular DOX accumulation and synergistically induce the cell apoptosis in DOX‐resistant MCF‐7/ADR cells. Meanwhile, the tumor site‐specific chemotherapy combined with hyperthermia effect induces significant inhibition of MCF‐7/ADR tumor growth in tumor‐bearing mice. These results demonstrate that the well‐designed IR‐780 loaded polymeric prodrug micelles for hyperthermia‐assisted site‐specific chemotherapy present an effective approach to reverse drug resistance.     

Polymeric Micelle‐Mediated Delivery of DNA‐Targeting Organometallic Complexes for Resistant Ovarian Cancer Treatment

Three half‐sandwich iridium and ruthenium organometallic complexes with high cytotoxicity are synthesized, and their anticancer mechanisms are elucidated. The organometallic complexes can interact with DNA through coordination or intercalation, thereby inducing apoptosis and inhibiting proliferation of resistant cancer cells. The organometallic complexes are then incorporated into polymeric micelles through the polymer‐metal coordination between poly(ethylene glycol)‐b‐poly(glutamic acid) [PEG‐b‐P(Glu)] and organometallic complexes to further enhance their anticancer effects as a result of the enhanced permeability and retention effect. The micelles with particle sizes of ≈60 nm are more efficiently internalized by cancer cells than the corresponding complexes, and selectively dissociate and release organometallic anticancer agents within late endosomes and lysosomes, thereby enhancing drug delivery to the nuclei of cancer cells and facilitating their interactions with DNA. Thus, the micelles display higher antitumor activity than the organometallic complexes alone with a lack of the systemic toxicity in a mouse xenograft model of cisplatin‐resistant human ovarian cancer. These results suggest that the polymeric micelles carrying anticancer organometallic complexes provide a promising platform for the treatment of resistant ovarian cancer and other hard‐to‐treat solid tumors.     

Site‐Specific Construction of Long‐Term Drug Depot for Suppression of Tumor Recurrence

Local tumor recurrence after surgical resection is a critical concern in cancer therapy, and the current treatments, such as postsurgical chemotherapy, still show undesired side effects. Here a nonimplant strategy (transformation induced localization, TIL) is presented to in situ construct long‐term retentive drug depots, wherein the sustained drug release from fibrous drug depots results in highly efficient suppression of postsurgical local tumor relapse. The peptide‐based prodrug nanoparticles show favorable tumor targeting and instantly reorganize into fibrous nanostructures under overexpressed enzyme, realizing the construction of long‐term drug depot in the tumor site. After the resection surgery, the remnant cancer cells are still inhibited by the sustained drug release from the fibrous prodrug depot, effectively preventing postsurgical local recurrences. This TIL strategy shows great potential in cancer recurrence therapy and offers a novel perspective for constructing functional biomaterials in vivo.     

Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

Targeted anticancer prodrug with mesoporous silica nanoparticles as vehicles

A targeted anticancer prodrug system was fabricated with 180?nm mesoporous silica nanoparticles (MSNs) as carriers. The anticancer drug doxorubicin (DOX) was conjugated to the particles through an acid-sensitive carboxylic hydrazone linker which is cleavable under acidic conditions. Moreover, folic acid (FA) was covalently conjugated to the particle surface as the targeting ligand for folate receptors (FRs) overexpressed in some cancer cells. The in vitro release profiles of DOX from the MSN-based prodrug systems showed a strong dependence on the environmental pH values. The fluorescent dye FITC was incorporated in the MSNs so as to trace the cellular uptake on a fluorescence microscope. Cellular uptakes by HeLa, A549 and L929 cell lines were tested for FA-conjugated MSNs and plain MSNs respectively, and a much more efficient uptake by FR-positive cancer cells (HeLa) can be achieved by conjugation of folic acid onto the particles because of the folate-receptor-mediated endocytosis. The cytotoxicities for the FA-conjugated MSN prodrug, the plain MSN prodrug and free DOX against three cell lines were determined, and the result indicates that the FA-conjugated MSN prodrug exhibits higher cytotoxicity to FR-positive cells, and reduced cytotoxicity to FR-negative cells. Thus, with 180?nm MSNs as the carriers for the prodrug system, good drug loading, selective targeting and sustained release of drug molecules within targeted cancer cells can be realized. This study may provide useful insights for designing and improving the applicability of MSNs in targeted anticancer prodrug systems.     

Acid-activatable doxorubicin prodrug micelles with folate-targeted and ultra-high drug loading features for efficient antitumor drug delivery

Stimuli-responsive nanomedicine shows high therapeutic effects and low side effects to tumor cells and tissues, representing a preferable therapeutics for cancer therapy. Herein, we design an acid-stimuli-responsive doxorubicin polymeric prodrug (OM@DOX), and this amphiphilic prodrug has a unique chemical structure with prominent advantages, including high drug loading rate (as high as 61.5 wt%), pH-triggered drug release and targeted access to cells. This smart polymeric prodrug has a preferable size of ~40 nm and strong micellar stability in aqueous solution, which is benefited to the long blood circulation and efficient extravasation from tumor vessel. Moreover, the prodrug micelles showed a higher cytotoxicity against tumor cells (HeLa cells) than normal cells (L929 cells), likely suggesting the potential tumor-specific targeting ability. To render this prodrug micelles with targeting function, folic acid (FA) molecules conjugated prodrug (FA-OM@DOX) further showed selectively higher cytotoxicity to KB tumor cells (FA-receptor-positive) than A549 tumor cells (FA-receptor-negative). Considering the rapidly cell-penetrating ability and aforementioned features, we believe that the present prodrug strategy has the potential as a promising nanomedicine and providing inspired insights to design multifunctional drug delivery nanoplatforms.     

Intracellular Delivery of a Planar DNA Origami Structure by the Transferrin‐Receptor Internalization Pathway

DNA origami provides rapid access to easily functionalized, nanometer‐sized structures making it an intriguing platform for the development of defined drug delivery and sensor systems. Low cellular uptake of DNA nanostructures is a major obstacle in the development of DNA‐based delivery platforms. Herein, significant strong increase in cellular uptake in an established cancer cell line by modifying a planar DNA origami structure with the iron transport protein transferrin (Tf) is demonstrated. A variable number of Tf molecules are coupled to the origami structure using a DNA‐directed, site‐selective labeling technique to retain ligand functionality. A combination of confocal fluorescence microscopy and quantitative (qPCR) techniques shows up to 22‐fold increased cytoplasmic uptake compared to unmodified structures and with an efficiency that correlates to the number of transferrin molecules on the origami surface.     

TPGS‐Functionalized Polydopamine‐Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance

A nanocarrier system of d ‐a‐tocopheryl polyethylene glycol 1000 succinate (TPGS)‐functionalized polydopamine‐coated mesoporous silica nanoparticles (NPs) is developed for sustainable and pH‐responsive delivery of doxorubicin (DOX) as a model drug for the treatment of drug‐resistant nonsmall cell lung cancer. Such nanoparticles are of desired particle size, drug loading, and drug release profile. The surface morphology, surface charge, and surface chemical properties are also successfully characterized by a series of techniques such as transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), Brunauer‐Emmett‐Teller (BET) method, thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FTIR). The normal A549 cells and drug‐resistant A549 cells are employed to access the cytotoxicity and cellular uptake of the NPs. The therapeutic effects of TPGS‐conjugated nanoparticles are evaluated in vitro and in vivo. Compared with free DOX and DOX‐loaded NPs without TPGS ligand modification, MSNs‐DOX@PDA‐TPGS exhibits outstanding capacity to overcome multidrug resistance and shows better in vivo therapeutic efficacy. This splendid drug delivery platform can also be sued to deliver other hydrophilic and hydrophobic drugs.     

Effect of poly‐glutamate on uptake efficiency and cytotoxicity of cell penetrating peptides

Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various molecules. An ideal CPP‐peptide should not display any toxicity against cancer cells as well as healthy cells and efficiently enter into the cell. Because of the cationic nature and the intrinsic vector capabilities, these peptides can cause cytotoxicity. One of the possible reasons for toxicity of CPPs is direct translocation and consequently, pore formation on the plasma membrane. In this study it was demonstrated that interaction of poly‐glutamate with CPP considerably reduced their cytotoxicity in A549 cell. This strategy could be useful for efficient drug delivery mediated by CPP.Inspec keywords: cellular biophysics, polymers, drug delivery systems, biomedical materials, toxicology, molecular biophysicsOther keywords: drug delivery, A549 cell, plasma membrane, pore formation, cancer cells, poly‐glutamate, cytotoxicity, uptake efficiency, cell penetrating peptides     

Smart Drug Delivery Nanocarriers with Self‐Assembled DNA Nanostructures

Self‐assembled DNA nanostructures have emerged as a type of nano‐biomaterials with precise structures, versatile functions and numerous applications. One particularly promising application of these DNA nanostructures is to develop universal nanocarriers for smart and targeted drug delivery. DNA is the genetic material in nature, and inherently biocompatible. Nevertheless, cell membranes are barely permeable to naked DNA molecules, either single‐ or double‐ stranded; transport across the cell membrane is only possible with the assistance of transfection agents. Interestingly, recent studies revealed that many DNA nanostructures could readily go into cells with high cell uptake efficiency. In this Progress Report, we will review recent advances on using various DNA nanostructures, e.g., DNA nanotubes, DNA tetrahedra, and DNA origami nanorobot, as drug delivery nanocarriers, and demonstrate several examples aiming at therapeutic applications with CpG‐based immunostimulatory and siRNA‐based gene silencing oligonucleotides.     

Bioinspired Nano‐Prodrug with Enhanced Tumor Targeting and Increased Therapeutic Efficiency

Nanotechnology‐based drug delivery has a great potential to revolutionize cancer treatment by enhancing anticancer drug efficacy and reducing drug toxicity. Here, a bioinspired nano‐prodrug (BiNp) assembled by an antineoplastic peptidic derivative (FA‐KLA‐Hy‐DOX), a folate acid (FA)‐incorporated proapoptotic peptide (KLAKLAK)₂ (KLA) to doxorubicin (DOX) via an acid‐labile hydrozone bond (Hy) is constructed. The hydrophobic antineoplastic agent DOX is efficiently shielded in the core of nano‐prodrug. With FA targeting moieties on the surface, the obtained BiNp shows significant tumor‐targeting ability and enhances the specific uptake of cancer cells. Upon the trigger by the intracellular acidic microenvironment of endosomes, the antineoplastic agent DOX is released on‐demand and promotes the apoptosis of cancer cells. Simultaneously, the liberated FA‐KLA can induce the dysfunction of mitochondria and evoke mitochondria‐dependent apoptosis. In vitro and in vivo results show that the nano‐prodrug BiNp with integrated programmed functions exhibits remarkable inhibition of tumor and achieves a maximized therapeutic efficiency with a minimized side effect.     

Functional DNA Nanostructures for Photonic and Biomedical Applications

DNA nanostructures, especially DNA origami, receive close interest because of the programmable control over their shape and size, precise spatial addressability, easy and high‐yield preparation, mechanical flexibility, and biocompatibility. They have been used to organize a variety of nanoscale elements for specific functions, resulting in unprecedented improvements in the field of nanophotonics and nanomedical research. In this review, the discussion focuses on the employment of DNA nanostructures for the precise organization of noble metal nanoparticles to build interesting plasmonic nanoarchitectures, for the fabrication of visualized sensors and for targeted drug delivery. The effects offered by DNA nanostructures are highlighted in the areas of nanoantennas, collective plasmonic behaviors, single‐molecule analysis, and cancer‐cell targeting or killing. Finally, the challenges in the field of DNA nanotechnology for realistic application are discussed and insights for future directions are provided.     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

Facile Fabrication of Tumor Redox‐Sensitive Nanoassemblies of Small‐Molecule Oleate Prodrug as Potent Chemotherapeutic Nanomedicine

The conjugate of paclitaxel (PTX) and docosahexaenoic acid has entered into clinical trials. However, the most recent clinical outcomes fell short of expectations, due to the extremely slow drug release from the hydrophobic conjugates. Herein, a novel prodrug‐based nanoplatform self‐assembled by the disulfide bond linked conjugates of PTX and oleic acid for rapid and differential release of PTX in tumor cells is reported. This redox‐responsive prodrug‐nanosystem demonstrates multiple therapeutic advantages, including one‐step facile fabrication, high drug‐loading efficiency (56%, w/w), on‐demand drug release responding to redox stimuli, as well as favorable cellular uptake and biodistribution. These advantages result in significantly enhanced antitumor efficacy in vivo, with the tumor almost completely disappearing in mice. Such a uniquely engineered prodrug‐nanosystem has great potential to be used as potent chemotherapeutic nanomedicine in clinical cancer therapy.     

Tumor Microenvironment‐Activatable Prodrug Vesicles for Nanoenabled Cancer Chemoimmunotherapy Combining Immunogenic Cell Death Induction and CD47 Blockade

Chemoimmunotherapy is reported to activate a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), which has initiated a number of clinical trials. However, current chemoimmunotherapy is restricted to a small fraction of patients due to low drug delivery efficacy and immunosuppression within the tumor microenvironment. A tumor microenvironment‐activatable prodrug vesicle for cancer chemoimmunotherapy using ICD is herein reported. The prodrug vesicles are engineered by integrating an oxaliplatin (OXA) prodrug and PEGylated photosensitizer (PS) into a single nanoplatform, which show tumor‐specific accumulation, activation, and deep penetration in response to the tumoral acidic and enzymatic microenvironment. It is demonstrated that codelivery of OXA prodrug and PS can trigger ICD of the tumor cells by immunogenic cells killing. The combination of prodrug vesicle‐induced ICD with Î ± CD47‐mediated CD47 blockade further facilitates dendritic cell (DC) maturation, promotes antigen presentation by DCs, and eventually propagates the antitumor immunity of ICD. CD47 blockade and ICD induction efficiently inhibit the growth of both primary and abscopal tumors, suppress tumor metastasis, and prevent tumor recurrence. Collectively, these results imply that boosting antitumor immunity using ICD induction and suppressing tumor immune evasion via CD47 blockade might be promising for improved cancer chemoimmunotherapy.     

Cocktail Strategy Based on Spatio‐Temporally Controlled Nano Device Improves Therapy of Breast Cancer

Metastatic breast cancer may be resistant to chemo‐immunotherapy due to the existence of cancer stem cells (CSC). Also, the control of particle size and drug release of a drug carrier for multidrug combination is a key issue influencing the therapy effect. Here, a cocktail strategy is reported, in which chemotherapy against both bulk tumor cells and CSC and immune checkpoint blockade therapy are intergraded into one drug delivery system. The chemotherapeutic agent paclitaxel (PTX), the anti‐CSC agent thioridazine (THZ), and the PD‐1/PD‐L1 inhibitor HY19991 (HY) are all incorporated into an enzyme/pH dual‐sensitive nanoparticle with a micelle–liposome double‐layer structure. The particle size shrinks when the nanoparticle transfers from circulation to tumor tissues, favoring both pharmacokinetics and cellular uptake, meanwhile achieving sequential drug release where needed. This nano device, named PM@THL, increases the intratumoral drug concentrations in mice and exhibits significant anticancer efficacy, with tumor inhibiting rate of 93.45% and lung metastasis suppression rate of 97.64%. It also reduces the proportion of CSC and enhances the T cells infiltration in tumor tissues, and thus prolongs the survival of mice. The cocktail therapy based on the spatio‐temporally controlled nano device will be a promising strategy for treating breast cancer.     

Photosensitizer‐Incorporated Quadruplex DNA‐Gated Nanovechicles for Light‐Triggered,Targeted Dual Drug Delivery to Cancer Cells

A novel light‐operated vehicle for targeted intracellular drug delivery is constructed using photosensitizer‐incorporated G‐quadruplex DNA‐capped mesoporous silica nanoparticles. Upon light irradiation, the photosensitizer generates ROS, causing the DNA capping to be cleaved and allowing cargo to be released. Importantly, this platform makes it possible to develop a drug‐carrier system for the synergistic combination of chemotherapy and PDT for cancer treatment with spatial/temporal control. Furthermore, the introducing of targeting ligands further improves tumor targeting efficiency. The excellent biocompatibility, cell‐specific intracellular drug delivery, and cellular uptake properties set up the basis for future biomedical application that require in vivo controlled, targeted drug delivery.