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Cancer nanomedicines require different, even opposite, properties to voyage the cascade drug delivery process involving a series of biological barriers. Currently-approved nanomedicines can only alleviate adverse effects but cannot improve patient survival because they fail to meet all the requirements. Therefore, nanocarriers with synchronized functions are highly requisite to capacitate efficient drug delivery and enhanced therapeutic efficacies. This perspective article summarizes recent advances in the two main strategies for nanomedicine design, the All-in-One approach (integration of all the functions in one system) and the One-for-All approach (one functional group with proper affinity enables all the functions), and presents our views on future nanomedicine development.

Active transcytosis has recently sparked great interest in drug delivery as a novel route for tumor extravasation and infiltration. However, the rational design of transcytosis-inducing nanomedicines remains challenging. We recently demonstrated that the γ-glutamyl transpeptidase (GGT)-responsive polymer cationization induced efficient adsorption-mediated transcytosis (AMT). However, it remains unclear how the nanomedicines' physicochemical properties influence the GGT-responsive cationization and induced transcytosis behaviors. Herein, through a combination of experimental techniques and molecular dynamics (MD) simulations, we find that the random copolymers with high hydrophobic monomers tend to form compact structures accessible to the catalytic site of GGT, leading to a fast cationization and thus high transcytosis efficiency, while the homopolymers of the hydrophilic GGT-sensitive monomers have elongated structures unable to enter the active site and thus exhibit poor GGT sensitivity. As a result, the more hydrophobic polymer-drug conjugates with high camptothecin contents exhibit higher GGT-responsive activity, which in turn leads to faster cationization and cellular internalization, enhanced tumor infiltration, and more potent antitumor activity. These findings indicate the hydrophobicity is a main parameter determining the GGT catalytic activity and transcytosis efficiency of the GGT-activatable co(homo)polymers, providing guidelines for the rational design of GGT-induced charge reversal carriers for transcytotic nanomedicines.

Cancer drug delivery systems often suffer from premature drug leakage during transportation and/or inefficient drug release within cancer cells. We present here a polymeric prodrug nanoassembly that addresses these problems simultaneously. This nanoassembly comprises a polymeric prodrug with novel trivalent phenylboronate moieties for drug conjugation via ether linkages, as well as β-lapachone (Lapa). While the ether linkage enables nearly no drug release under physiological conditions, the Lapa molecules can induce the reactive oxygen species (ROS) burst specifically in cancer cells via NAD(P)H: quinone oxidoreductase-1 catalysis, which triggers the cleavage of the ether bonds and thus cascade amplification drug release in cancer cells. As a result, the nanoassemblies exhibit much higher cytotoxicity against cancer cells than normal cells, and also increased therapeutic efficacy and reduced side effects compared to the clinically used irinotecan. We anticipate that this strategy can be applied to other drug delivery platforms to enable more precise drug release.

Herein, we report a class of distinctive supramolecular nanostructures in situ-generated from the cationic ring-opening polymerization of a particular 2-oxazoline monomer, i.e., 2-(

Subcutaneous injection of insulin is the current standard medication for many diabetic patients. Convenient and painless noninvasive transdermal insulin delivery has long been pursued but yet succeeded due to no such technologies for large biomacromolecules. We find a tertiary amine oxide-based polyzwitterion, OPDMA, that can efficiently penetrate both the stratum corneum (SC) and viable epidermis into circulation. So its conjugate with insulin, OPDMA-I, applied on the skin can exhibit hypoglycemic effects as efficiently as subcutaneously injected insulin in type-1 diabetic mice and minipigs. The unique pH-dependent cationic-to-zwitterionic transition of OPDMA in the characteristic acidic-to-neutral pH gradient from the skin surface to deep SC enables fast transdermal delivery of OPDMA and its conjugate. On the skin, OPDMA binds to carboxylic acids in the acidic sebum layer, enriching OPDMA-I on the SC. As pH increases in deeper SC layers, binding between OPDMA-I and the skin weakens gradually, allowing for diffusion through inter-corneocyte gaps and penetration into viable epidermis and finally entering the systemic circulation via dermal lymphatic vessels. This process does not alter SC microstructures or cause any physiological changes in the skin. This study represents a groundbreaking example of noninvasive transdermal protein delivery.

Nanocarriers have been employed extensively to enhance drug delivery efficacy and reduce the side effect. However, carrier materials for drug delivery have challenging aspects, including safety concerns, low drug content, complexity in preparation, and low reproducibility. Herein, we propose a facile, universal, and green preparation way to use natural polyphenols to build platinum nanocomplex with stable structure, proper size, and high Pt content. The nanocomplexes are constructed by metal-polyphenol coordination using natural polyphenols and 1,2-diaminocyclohexane-Pt (II), enabling dual-responsive drug release behavior. For proof of concept, we demonstrate the antitumor activity of the Pt nanocomplex using a representative tannic acid-Pt nanocomplex (denoted as PTI). PTI can induce intensive tumor cell apoptosis, trigger immunogenic cell death (ICD), remarkably promote cytotoxic T lymphocytes (CTLs) infiltration in tumors, and significantly reduce immunosuppression of the tumor microenvironments, thus stimulating potent antitumor immune responses and showing effective antitumor activity by synergizing immune checkpoint blockade (ICB) therapy.

Copper (ii) orcis-platinum complexation nanogels for tumor metal delivery to potentiate the antitumor efficacy of DSF.

Tumor enzyme-responsive charge-reversal carriers can induce efficient transcytosis and lead to efficient tumor infiltration and potent anticancer efficacy. However, the correlations of molecular structure with charge-reversal property, tumor penetration, and drug delivery efficiency are unknown. Herein, aminopeptidase N (APN)-responsive conjugates were synthesized to investigate these correlations. We found that the monomeric unit structure and the polymer chain structure determined the enzymatic hydrolysis and charge-reversal rates, and accordingly, the transcytosis and tumor accumulation and penetration of the APN-responsive conjugates. The conjugate with moderate APN responsiveness balanced the in vitro transcytosis and in vivo overall drug delivery process and achieved the best tumor delivery efficiency, giving potent antitumor efficacy. This work provides new insight into the design of tumor enzyme-responsive charge-reversal nanomedicines for efficient cancer drug delivery.

Ligand/receptor-mediated targeted drug delivery has been widely recognized as a promising strategy for improving the clinical efficacy of nanomedicines but is attenuated by the binding of plasma protein on the surface of nanoparticles to form a protein corona. Here, it is shown that ultrasonic cavitation can be used to unravel surface plasma coronas on liposomal nanoparticles through ultrasound (US)-induced liposomal reassembly. To demonstrate the feasibility and effectiveness of the method, transcytosis-targeting-peptide-decorated reconfigurable liposomes (LPGLs) loaded with gemcitabine (GEM) and perfluoropentane (PFP) are developed for cancer-targeted therapy. In the blood circulation, the targeting peptides are deactivated by the plasma corona and lose their targeting capability. Once they reach tumor blood vessels, US irradiation induces transformation of the LPGLs from nanodrops into microbubbles via liquid-gas phase transition and decorticate the surface corona by reassembly of the lipid membrane. The activated liposomes regain the capability to recognize the receptors on tumor neovascularization, initiate ligand/receptor-mediated transcytosis, achieve efficient tumor accumulation and penetration, and lead to potent antitumor activity in multiple tumor models of patient-derived tumor xenografts. This study presents an effective strategy to tackle the fluid biological barriers of the protein corona and develop transcytosis-targeting liposomes for active tumor transport and efficient cancer therapy.

Fluorescent imaging with fluorophores has become a powerful way to explore complex biological systems and visualize nanoparticles for drug delivery. However, it is challenging to develop fluorophores with ideal physical and optical properties. We report a method to synthesize cyanine nanodots with a single-molecule structure, well-defined particle size, customizable fluorescent spectrum, and bright and stable fluorescence. These cyanine nanodots are acquired by the divergent synthesis of cyanine-dye-cored polylysine (PLL) dendrimers. We demonstrated the feasibility of the method by synthesizing cyanine 3 (Cy3), cyanine 5 (Cy5), or cyanine 7 (Cy7) cored single-molecule nanodots up to eight generations with a size of around 11 nm. We show that these cyanine nanodots are capable of multiple biomedical applications, including multicolor cellular tracing and cancer imaging. These cyanine nanodots possess many merits of organic dots and quantum dots that are promising for future application.

Encapsulation and controlled release of volatile molecules such as fragrances in a designed manner is important but challenging for the flavor and fragrance industry. Here, we report the tuning release of volatile molecules by postsynthetic modification of an amine-terminated metal-organic framework (MOF) MIL-101-NH2. By amidation, we obtained three MIL-101 MOFs, the trimethylacetamide-terminated TC-MIL-101, the benzamide-terminated BC-MIL-101, and the oxalic acid monoamide-terminated OC-MIL-101. All the MOFs can efficiently encapsulate volatile molecules. Moreover, we demonstrate that the release profile of volatiles can be widely tuned to sustain the release in several days to months and even over a year using different modified MIL-101 MOFs. We show that the release profiles are correlated with the binding energies between the guest volatiles and pores in MOFs. The pore diffusion and the synergistic transport are the rate-limiting step of the guest molecules from the modified MOFs.

Cisplatin (CDDP) is a potent first-line antitumor drug but suffers severe side effects and poor pharmacokinetics. Its complexation with polycarboxylic acids, such as polyglutamic acids, is generally used to fabricate nanoformulations for CDDP delivery; however, the multiple strong complexations makes intracellular drug release slow. Herein, we report a novel polyphenol-metal coordination method to fabricate CDDP-incorporated core-shell nanoparticles, which are stable in blood circulation but dissociate in the tumor. Methoxyl-PEG terminated with one or two gallic acids (PEG-GA or PEG-GA2) complexed CDDP and produced well-defined nanoparticles (PEG-GAx/Pt) with CDDP loading contents as high as 17.7% to 29.8%. The PEG-GAx/Pt nanoparticles were very stable in the physiological conditions and had slow blood clearance and efficient tumor accumulation, but dissociated quickly and released CDDP in response to the tumor acidity or elevated levels of reactive oxygen species (ROS). PEG-GAx/Pt nanoparticles exhibited improved antitumor efficiency against 4 T1 breast cancer and A549 lung carcinoma with much-reduced toxicity compared to free CDDP. The work demonstrates a new strategy of cisplatin-polyphenol coordination for developing platinum drugs' nanomedicines.

Albumin-based nanomedicines are important nanoplatforms for cancer drug delivery. The drugs are either physically encapsulated or covalently conjugated to albumin or albumin-based nanosystems. Physical encapsulation is advantageous due to requiring no chemical modification of drug molecules, but many drugs, for instance, camptothecin (CPT) and curcumin (CCM), though very hydrophobic, can't be loaded in or form nanoformulations with albumin. Herein, we demonstrate prodrugs readily binding to proteins via iminoboronates and forming nanoparticles for cancer drug delivery. CPT and CCM were functionalized with 2-acetylphenylboronic acid (2-APBA) to produce prodrugs CPT-SS-APBA and CCM- APBA. The prodrugs bound to bovine serum albumin (BSA) via formation of iminoboronates and the produced BSA/prodrug readily self-assembled into well-defined nanoparticles with high loading efficiency, improved colloidal stability, and much-improved pharmacokinetics. The nanoparticles effectively released drugs in the intracellular acidic environment or the cytosol rich in glutathione (GSH). In vivo, the nanoparticles showed enhanced anticancer efficacy compared with clinically used irinotecan or sorafenib in subcutaneous 4 T1 or HepG2 tumor models. This work demonstrates a versatile protein-binding prodrug platform applicable to protein-based drug formulations and even antibody-drug conjugates.

Amphiphilic block copolymer prodrugs, which can self-assemble into stable core–shell micelles, have been widely used for anticancer drug delivery. However, a major challenge is to design drug-conjugating linkers stable in blood but selectively cleavable inside tumor cells for drug release. Hydrogen sulfide (H2S) is an important gaseous signaling molecule involved in tumor formation, development, and metastasis and is highly upregulated in multiple cancer types. Accordingly, we designed an H2S-sensitive azide-based linker and used it to conjugate paclitaxel (PTX) to a prodrug copolymer (PEG-PAMPTX). The amphiphilic PEG-PAMPTX self-assembled into micelles with a diameter of about 30 nm, stable under normal physiological conditions for long blood circulation. Once in tumors, the intratumoral H2S selectively reduced the azide group into an amino group, triggering self-cyclization to release PTX rapidly. As a result, the micelles showed remarkably enhanced antitumor activity compared to Taxol in a triple-negative breast cancer orthotopic model.

Extravasation is the first step for nanomedicines in circulation to reach targeted solid tumors. Traditional nanomedicines have been designed to extravasate into tumor interstitium through the interendothelial gaps previously assumed rich in tumor blood vessels, i.e., the enhanced permeability and retention (EPR) effect. While the EPR effect has been validated in animal xenograft tumor models, accumulating evidence implies that the EPR effect is very limited and highly heterogeneous in human tumors, leading to highly unpredictable and inefficient extravasation and thus limited therapeutic efficacy of nanomedicines, including those approved in clinics. Enabling EPR-independent extravasation is the key to develop new generation of nanomedicine with enhanced efficacy. Transcytosis of tumor endothelial cells can confer nanomedicines to actively extravasate into solid tumors without relying on the EPR effect. Here, we review and prospectthe development of transcytosis-inducing nanomedicines, in hope of providing instructive insights for design of nanomedicines that can undergo selective transcellular transport across tumor endothelial cells, and thus inspiring the development of next-generation nanomedicines for clinical translation.

Specific labeling of biomarkers with bright and high photostable fluorophores is vital in fluorescent imaging applications. Here, we report a general strategy to develop single-molecule dendritic nanodots with finely tunable optical properties for in vivo fluorescent imaging. The well-defined nanodots are based on the divergent growth of biodegradable polylysine dendrimers with a fluorophore as the core. By tuning the size and surface chemistry, we obtained fluorescent nanodots with excellent brightness and photostability, favorable pharmacokinetics, and multivalent tumor-targeting capability. The nanodots provided robust, stable, long-lasting, and specific fluorescence enhancement in tumor tissue with an in situ tumor-to-normal ratio (TNR) of ∼3 and lasting over 5 days and an ex vivo TNR up to ∼17, holding considerable promise for cancer imaging and image-guided surgery. This strategy significantly improves the in vivo performance of fluorophores and can be applied to other modality imaging probes.

The dense fibrotic stroma in pancreatic ductal adenocarcinoma (PDA) resists drug diffusion into the tumor and leads to an unsatisfactory prognosis. To address this problem, we demonstrate a dendrimer-camptothecin (CPT) conjugate that actively penetrates deep into PDA tumors through γ-glutamyl transpeptidase (GGT)-triggered cell endocytosis and transcytosis. The dendrimer-drug conjugate was synthesized by covalent attachment of CPT to polyamidoamine (PAMAM) dendrimers through a reactive oxygen species (ROS)-sensitive linker followed with surface modification with glutathione. Once the conjugate was delivered to the PDA tumor periphery, the overexpressed GGT on the vascular endothelial cell or tumor cell triggers the γ-glutamyl transfer reactions of glutathione to produce primary amines. The positively charged conjugate was rapidly internalized via caveolae-mediated endocytosis and followed by vesicle-mediated transcytosis, augmenting its deep penetration within the tumor parenchyma and releasing active CPT throughout the tumor after cleavage by intracellular ROS. The dendrimer-drug conjugate exhibited high antitumor activity in multiple mice tumor models, including patient-derived PDA xenograft and orthotopic PDA cell xenograft, compared to the standard first-line chemotherapeutic drug (gemcitabine) for advanced pancreatic cancer. This study demonstrates the high efficiency of an active tumor-penetrating dendrimer-drug conjugate via transcytotic transport with ROS-responsive drug release for PDA therapy.

Cationic polymers condense nucleic acids into nanosized complexes (polyplexes) that are widely explored for nonviral gene delivery, but their strong electrostatic binding with DNA causes inefficient intracellular gene release and translation and thereby unsatisfactory gene transfection efficiencies. Facilitated intracellular dissociation of polyplexes by making the polymer undergo positive-to-negative/neutral charge reversal can effectively solve these problems, but they must be sufficiently stable during the delivery. Herein, we report the first glutathione (GSH)-specific intracellular labile polyplexes for cancer-targeted gene delivery. The polymers are made from p-(2,4-dinitrophenyloxybenzyl)-ammonium cationic moieties, whose p-2,4-dinitrophenyl ether is cleaved specifically by GSH, rather than other biological thiols, triggering the conversion of the ammonium cation into the carboxylate anion and thus the fast intracellular DNA release of the polyplexes. Furthermore, the polyplexes coated with PEG-functionalized lipids are stable in biological fluids to gain long blood circulation for tumor accumulation. Thus, the efficient tumor accumulation and cell transfection of the polyplexes loaded with the tumor suicide gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) give rise to potent antitumor activity similar to that of the first-line chemotherapy drug paclitaxel but with much less adverse effects.

Nanotechnology has a remarkable impact on the preclinical development of future medicines. However, the complicated preparation and systemic toxicity to living systems prevent them from translation to clinical applications. In the present report, we developed a polyepicatechin-based on/off switchable ultra-sensitive magnetic resonance imaging (MRI) visible theranostic nanoparticle (PEMN) for image-guided photothermal therapy (PTT) using our strategy of integrating polymerization and biomineralization into the protein template. We have exploited natural polyphenols as the near infra-red (NIR) switchable photothermal source and MnO2 for the MRI-guided theranostics. PEMN demonstrates excellent MRI contrast ability with a longitudinal relaxivity value up to 30.01 mM-1 s-1. PEMN has shown great tumor inhibition on orthotopic breast tumors and the treatment could be made switchable with an on/off interchangeable mode as needed. PEMN was found to be excretable mainly through the kidneys, avoiding potential systemic toxicity. Thus, PEMN could be extremely useful for developing on-demand therapeutics via'see it and treat it' means with distinguished MRI capability and on/off switchable photothermal properties.

The research on advanced functional polymers is being driven by the fast-growing demand for new functional materials that can be used in revolutionary technologies. Polymers can be endowed with functions by using certain special preparation methods or by introducing functional groups or fillers into materials. These functions are either intrinsically possessed by materials or actuated by external stimuli. In this review, we present an overview of the recent developments made in the research hotspots of functional polymers, encompassing polymerization methodologies, luminescent polymers, photovoltaic polymers, other electronic and optical polymers (including low-k polyimides and second-order nonlinear optical polymers), biorelated polymers (particularly those for biomedical applications), supramolecular polymers, stimuli-responsive polymers, shape-memory polymers, separation polymer membranes, energy storage polymers, and covalent organic framework polymers. The concepts, design strategies at the molecular level, preparation methods, classifications, properties, potential applications, and recent progress made in such polymers are summarized. Challenges and future perspectives of each type of functional polymers are also addressed, including research efforts regarding the design and fabrication of functional polymers for serving the increasing demand for new materials.

Nanotheranostics (combined diagnosis and therapy) is emerging as an integral part of future therapeutic strategies. However, the development and fabrication of a nanotheranostic module involves multistep processes and always faces formulation challenges. The complexity involved in its multi-step formulations hinders its reproducible industrial production and clinical translation. Therefore, a facile synthesis of multifunctional nanotheranostics is critical to its translational success. In this report, we have developed a one-pot facile strategy to prepare a MRI-visible photothermal theranostic switchable module (T-SWITCH). These nanoparticles are synthesized through polymerization of levodopa together with the reduction of KMnO4 in the presence of silk sericin for the formation of manganese dioxide particles within the T-SWITCH. The synthesized T-SWITCH showed a uniform size distribution of around 95.77 nm and high longitudinal relaxivity coefficient (r1) of up to 61.94 mM-1 s-1. The reported r1 of the T-SWITCH is exceedingly higher than that of any other previously reported manganese-based contrast agents with first-rate in vitro and in vivo contrast enhancement capability. The T-SWITCH can be activated to switch its therapeutic mode using near-infrared (NIR) light. It exhibited strong excitable absorption in the safer and biological NIR window between 650 and 900 nm. We have validated the significant anti-cancer therapeutic efficacy of T-SWITCH both in vitro and in vivo through switchable photothermal therapy.

We herein present a facile approach to create polydopamine (PDA) modified silica-based nanocarriers for use in the encapsulation and photothermally responsive release of the synthetic sandalwood odorant Sandalore (SA) as a low-volatile model fragrance. The method involves impregnating mesoporous silica nanoparticles with an ethanol solution of SA followed by surface functionalization via the in situ self-polymerization of dopamine under alkaline conditions. The resulted nanocomposites have high fragrance loading capacity with up to ∼85% by weight of SA relative to the silica matrix and are capable of effectively preserving the cargo in the dark or indoors. The aroma release was significantly accelerated upon illumination due to the photothermal heating effect of the PDA shell, which is proportional to the coating content and the irradiation intensity. Additionally, the emulated laundry tests showed that the composites exhibited a higher deposition efficiency on the fabric surface and better washing-resistance as compared to the control particles without PDA coating.

The clinical translation of nanomedicines has been impeded by the unfavorable tumor microenvironment (TME), particularly the tortuous vasculature networks, which significantly influence the transport and distribution of nanomedicines into tumors. In this work, a smart pH-responsive bortezomib (BTZ)-loaded polyhydralazine nanoparticle (PHDZ/BTZ) is presented, which has a great capacity to augment the accumulation of BTZ in tumors by dilating tumor blood vessels via specific release of vasodilator hydralazine (HDZ). The Lewis acid-base coordination effect between the boronic bond of BTZ and amino of HDZ empowered PHDZ/BTZ nanoparticles with great stability and high drug loading contents. Once triggered by the acidic tumor environment, HDZ could be released quickly to remodel TME through tumor vessel dilation, hypoxia attenuation, and lead to an increased intratumoral BTZ accumulation. Additionally, our investigation revealed that this pH-responsive nanoparticle dramatically suppressed tumor growth, inhibited the occurrence of lung metastasis with fewer side effects and induced immunogenic cell death (ICD), thereby eliciting immune activation including massive cytotoxic T lymphocytes (CTLs) infiltration in tumors and efficient serum proinflammatory cytokine secretion compared with free BTZ treatment. Thus, with efficient drug loading capacity and potent immune activation, PHDZ nanoparticles exhibit great potential in the delivery of boronic acid-containing drugs aimed at a wide range of diseases.

Disulfiram (DSF) is nontoxic and exerts anticancer activity by forming highly toxic chelates

Effective combination therapies are urgently needed to treat triple-negative breast cancer (TNBC), which is insensitive to the existing treatment regimens. However, the synergistic potency of traditional small-molecule combinations is limited in TNBC mainly due to mismatched molar ratios, inconsistent pharmacokinetics, and intratumoral accumulation of individual drugs. Here, we find that the autophagy inhibitor hydroxychloroquine (HCQ) and the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) exhibit synergistic effects when the molar ratio reaches 5:1. We further develop a glutathione-responsive self-assembled combination nanoparticle (Combo NP) to integrate individual HCQ and SN38 polymeric prodrugs at the optimized ratio. In TNBC cells treated with Combo NP, HCQ-mediated autophagy blockage significantly enhances the DNA damage and apoptotic effect of SN38, manifesting synergistically cytotoxic effects of Combo NP. In vivo evaluations show that Combo NP maintains the molar ratio of HCQ to SN38 within the synergistic range in mouse blood circulation and intratumoral tissues. More importantly, Combo NP elicits superior therapeutic benefit in metastatic TNBC models, compared to free drug combination as well as single drug nanoparticles. Taken together, our engineered nanosystem highlights a nanoprodrug-based chemosensitizing approach for improving the therapeutic response to TNBC, addressing the major challenges of the current combination therapy.

The adsorption-mediated transcytosis (AMT) induced by the electrostatic interaction between the positively charged surface of carriers and negatively charged cell membrane is a new paradigm enabling nanomedicine's tumor extravasation and infiltration. However, little is known about the correlation between the carrier's charge density and its AMT-induced tumor infiltration efficiency. Herein, we investigate the effect of the cationic polymer's charge on the AMT-induced tumor penetration ability using in vitro multilayer tumor spheroids (MTSs). A cationic polymer, polyethylenimine (PEI), is amidized with acetic anhydride to obtain acetylated PEIs (AcPEIs) with different cationic charge densities. As the amidization ratio increases, the AcPEIs' cytotoxicity, zeta potential, and cell-binding affinity significantly decrease. Notably, not only does the weak cell binding (AcPEIs with high acetylation degrees) lead to slow endocytosis and inefficient transcytosis, so does the strong cell-binding PEI. The PEI with 24% acetylation (AcPEI24%) is found to have the highest transcytosis efficiency because its balanced cell-binding affinity triggers fast adsorption-mediated endocytosis. The subsequent Golgi apparatus/endoplasmic reticulum-mediated exocytosis via extracellular vesicles leads to highly effective transcellular delivery and tumor penetration in MTSs. Therefore, the drug carrier's surface cationic charge density critically influences its AMT-induced tumor penetration efficiency. This study provides mechanistic insights into the design of drug-delivery systems with active transcytosis for improved tumor penetration and enhanced therapeutic efficiency.

Tumor-selective drug delivery could enhance anticancer efficacy and avoid drug side effects. However, because of tumor heterogeneity, current nanoparticle-based drug delivery systems rarely improve clinical outcomes significantly, commonly only reducing systemic toxicity. In this work, a new tumor-specific, tyrosinase-responsive cascade amplification release nanoparticle (TR-CARN) was developed to fulfill the needs for tumor-specific drug delivery and high efficacy cancer treatment. Tyrosinase (Tyr) is specifically expressed in melanomas and can catalyze acetaminophen (APAP) to increase reactive oxygen species (ROS). It was therefore utilized here to initiate the ROS amplification procedure. In TR-CARN, a ROS-responsive prodrug BDOX was loaded into an amphiphilic polymer, and APAP was linked to the polymer through a ROS-cleavable thioether bond. TR-CARN caused reduced side effects during the delivery because of the low toxicity of BDOX. Once TR-CARN entered into the tumor, endogenous ROS triggered initial APAP and BDOX release. Tyr-mediated ROS synthesis by APAP then accelerated APAP and BDOX release and toxification. Consequently, TR-CARN achieved melanoma-specific treatment of high efficacy through the cascade amplification strategy with enhanced biosafety.

Peptide dendrimers have a broad application in biomedical science due to their biocompatibility, diversity, and multifunctionality, but the precision synthesis of high-molecule weight peptide dendrimers remains challenging. We here report the facile and liquid-phase synthesis of molecular level precision and amino-acid built-in polylysine (PLL) dendrimers with molecular weights as high as ∼60 kDa. Three types of polyhedral oligosilsesquioxane (POSS)-cored PLL dendrimers with phenylalanine, tyrosine, or histidine as building blocks were synthesized. The precise structures of the dendrimers were confirmed by MALDI-TOF MS, GPC, and 1H NMR spectroscopy. The interior functionalized peptide dendrimers improved the encapsulation capability of SN38 and sustained the release profiles. Enhanced molecular interactions between the peptide dendrimers and drugs were explored by both NMR experiments and computer simulations. The peptide dendrimer/SN38 formulations showed potent antitumor activity against multiple cancer cell lines. We believe that this strategy can be applied to the synthesis of tailor-made functional peptide dendrimers for drug-specific delivery and other diverse biomedical applications.