Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency. METHODS: Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes. RESULTS: The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu. CONCLUSIONS: Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.

Self-Assembled Nanostructures of Homo-Oligopeptide as a Potent Ice Growth Inhibitor.

This study reports the formation of self-assembled nanostructures with homo-oligopeptides consisting of amino acids (i.e., alanine, threonine, valine, and tyrosine), the resulting morphologies (i.e., spherical shape, layered structure, and wire structure) in aqueous solution, and their potential as ice growth inhibitors. Among the homo-oligopeptides investigated, an alanine homo-oligopeptide (n = 5) with a spherical nanostructure showed the highest ice recrystallization inhibition (IRI) activity without showing a burst ice growth property and with low ice nucleation activity. The presence of nanoscale self-assembled structures in the solution showed superior IRI activity compared to an amino acid monomer because of the higher binding affinity of structures on the growing ice crystal plane. Simulation results revealed that the presence of nanostructures induced a significant inhibition of ice growth and increased lifetime of hydrogen bonding compared with unassembled homo-oligopeptide. These results envision extraordinary performance for self-assembled nanostructures as a desirable and potent ice growth inhibitor.

Perspectives for Improving the Tumor Targeting of Nanomedicine via the EPR Effect in Clinical Tumors.

Over the past few decades, the enhanced permeability and retention (EPR) effect of nanomedicine has been a crucial phenomenon in targeted cancer therapy. Specifically, understanding the EPR effect has been a significant aspect of delivering anticancer agents efficiently to targeted tumors. Although the therapeutic effect has been demonstrated in experimental models using mouse xenografts, the clinical translation of the EPR effect of nanomedicine faces several challenges due to dense extracellular matrix (ECM), high interstitial fluid pressure (IFP) levels, and other factors that arise from tumor heterogeneity and complexity. Therefore, understanding the mechanism of the EPR effect of nanomedicine in clinics is essential to overcome the hurdles of the clinical translation of nanomedicine. This paper introduces the basic mechanism of the EPR effect of nanomedicine, the recently discussed challenges of the EPR effect of nanomedicine, and various strategies of recent nanomedicine to overcome the limitations expected from the patients' tumor microenvironments.

Solution-Based One-Step Preparation of Three-Dimensional Self-Assembled Octadecyl Silica Nanosquare Plate and Microlamella Structures for Superhydrophobic and Icephobic Surfaces.

Icephobic surfaces have gained immense attention owing to their significant roles in decreasing the energy consumption of refrigerators and in improving safety issues by preventing the formation of ice on them. Superhydrophobic surfaces incorporating micro- or nanoscale roughness and hydrophobic functional groups have been shown to prevent ice accumulation. Herein, we report a simple, low-cost, and solution-based one-step process for the production of superhydrophobic surfaces with three-dimensional (3D) self-assembled structures. The controlled hydrolysis and polycondensation of n-octadecyltrichlorosilane (OTS-Cl) in an acetone solution produced a highly uniform superhydrophobic surface on various substrates such as glass, metals, and polymers without the limitation of the surface curvature structure. The as-prepared 3D self-assembled surface exhibited a very high contact angle of 161.7° and a low contact hysteresis of 1.47°. The solvent type, H2O content in acetone, and carbon chain length of the silane compound were critical in the formation of self-assembled nanostructures. The thickness of the superhydrophobic 3D self-assembled structure could be varied by controlling the surface properties of the glass substrate. In addition, a novel octadecyl silica nanosquare plate structure was formed as an intermediate for the microlamella structure. The water drop impact experiments on the 3D self-assembled superhydrophobic glass substrates at low temperatures (T < -25 °C) showed that the as-prepared superhydrophobic glass possessed a high impalement threshold for water contact, resulting in excellent and stable icephobic properties. The preparation method proposed in this study is scalable and can be used on a flat glass surface or in a glass vial inside a glass tube. Moreover, it can be applied to various substrates such as metals and polyurethane surfaces with curvature. Therefore, the solution-based self-assembly method proposed in this study is a promising approach to produce superhydrophobic and icephobic surfaces on a wide range of substrates regardless of their structure and properties.

Thiol-Responsive Gold Nanodot Swarm with Glycol Chitosan for Photothermal Cancer Therapy.

Photothermal therapy (PTT) is one of the most promising cancer treatment methods because hyperthermal effects and immunogenic cell death via PTT are destructive to cancer. However, PTT requires photoabsorbers that absorb near-infrared (NIR) light with deeper penetration depth in the body and effectively convert light into heat. Gold nanoparticles have various unique properties which are suitable for photoabsorbers, e.g., controllable optical properties and easy surface modification. We developed gold nanodot swarms (AuNSw) by creating small gold nanoparticles (sGNPs) in the presence of hydrophobically-modified glycol chitosan. The sGNPs assembled with each other through their interaction with amine groups of glycol chitosan. AuNSw absorbed 808-nm laser and increased temperature to 55 °C. In contrast, AuNSw lost its particle structure upon exposure to thiolated molecules and did not convert NIR light into heat. In vitro studies demonstrated the photothermal effect and immunogenic cell death after PTT with AuNSW. After intratumoral injection of AuNSw with laser irradiation, tumor growth of xenograft mouse models was depressed. We found hyperthermal damage and immunogenic cell death in tumor tissues through histological and biochemical analyses. Thiol-responsive AuNSw showed feasibility for PTT, with advanced functionality in the tumor microenvironment.

Recent Trends in In Situ Enzyme-Activatable Prodrugs for Targeted Cancer Therapy.

Enzyme-activatable anticancer prodrugs are modified medications that are composed of an anticancer drug, cleavable linker, and functional moiety. The purpose of such a prodrug structure is to generate multipurpose functions that traditional drugs cannot perform and to reduce the toxicity of conventional anticancer drugs by the mask of the cleavable linker. Once the cleavable linker is degraded via a specific chemical reaction in the cancer microenvironment, the cytotoxicity of the degraded prodrugs is selectively recovered. Among many factors that cleave the linker, we focus on the overexpressed enzymes in cancer. Because of the selective enzymatic degradation of the cleavable linker and the high local concentration of specific enzymes in cancer, the enzyme-activatable prodrugs could show low toxicity in normal tissues, while showing comparable anticancer effect in tumors. In addition, some prodrugs provide additional features, such as cancer imaging, drug release monitoring, tumor targeting, and enhanced stability, which conventional anticancer drugs cannot possess. In this review, we summarize currently developed enzyme-activatable prodrugs according to their activating enzymes, and categorize them by their additional functions, e.g. targeting, imaging, and delivery. This summary of enzyme-activatable prodrugs may help in the design of anticancer prodrugs, and in the establishment of a personalized cancer treatment strategy.

Antifreezing Gold Colloids.

Gold (Au) colloids are becoming ubiquitous across biomedical engineering, solar energy conversion, and nano-optics. Such universality has originated from the exotic plasmonic effect of Au colloids (i.e., localized surface plasmon resonance (LSPRs)) in conjunction with the versatile access to their synthetic routes. Herein, we introduce a previously undiscovered usage of Au colloids for advancing cryoprotectants with significant ice recrystallization inhibition (IRI). Oligopeptides inspired by the antifreeze protein (AFP) and antifreeze glycoprotein (AFGP) are attached onto the surface of well-defined Au colloids with the same sizes but different shapes. These AF(G)P-inspired Au colloids can directly adsorb onto a growing ice crystal via the synergistic interplay between hydrogen bonding and hydrophobic groups, in stark contrast to their bare Au counterparts. Dark-field optical microscopy analyses, benefiting from LSPR, allow us to individually trace the in situ movement of the antifreezing Au colloids during ice growth/recrystallization and clearly evidence their direct adsorption onto the growing ice crystal, which is consistent with theoretical predictions. With the assistance of molecular dynamics (MD) simulations, we evidently attribute the IRI of AF(G)P-inspired Au colloids to the Kelvin effect. We also exploit the IRI dependence on the Au colloidal shapes; indeed, the facet contacts between ice and Au colloids can be better than the point-like counterparts in terms of IRI. The design principles and predictive theory outlined in this work will be of broad interest not only for the fundamental exploration of the inhibition of ice growth but also for enriching the application of Au colloids.

A Comparative Study on Albumin-Binding Molecules for Targeted Tumor Delivery through Covalent and Noncovalent Approach.

Various types of albumin-binding molecules have been conjugated to anticancer drugs, and these modified prodrugs could be effective in cancer treatments compared to free anticancer drugs. However, the tumor targeting of albumin-binding prodrugs has not been clearly investigated. Herein, we examined the in vitro and in vivo tumor-targeting efficiency of three different albumin-binding molecules including albumin-binding peptide (DICLPRWGCLW: PEP), fatty acid (palmitic acid: PA), and maleimide (MI), respectively. In order to characterize the different targeting efficiency of albumin-binding molecules, PEP, PA, or MI was chemically labeled with near-infrared fluorescence (NIRF) dye, Cy5.5, in resulting PEP-Cy5.5, PA-Cy5.5, and MI-Cy5.5. These NIRF dye-labeled albumin-binding molecules were physically or chemically bound to albumin via gentle incubation in aqueous conditions in vitro. Notably, PA-Cy5.5 with reversible and multivalent binding affinities formed stable albumin complexes, compared to PEP-Cy5.5 and MI-Cy5.5, confirmed via surface plasmon resonance measurement, gel electrophoresis assay, and albumin-bound column-binding test. In tumor-bearing mice model, the different albumin-binding affinities of PA-Cy5.5, PEP-Cy5.5, and MI-Cy5.5 greatly contributed to their tumor-targeting ability. Even though the binding affinity of PEP-Cy5.5 and MI-Cy5.5 to albumin is higher than that of PA-Cy5.5 in vitro, intravenous PA-Cy5.5 showed a higher tumor-targeting efficiency in tumor-bearing mice compared to that of PEP-Cy5.5 and MI-Cy5.5. The reversible and multivalent affinities of albumin-binding molecules to native serum albumin greatly increased the pharmacokinetics and tumor-targeting efficiency in vivo.

Biomolecular Imaging of Regeneration of Zebrafish Caudal Fins Using High Spatial Resolution Ambient Mass Spectrometry.

We observed the molecular distribution changes that occurred during the regeneration of fresh zebrafish caudal fins using the recently developed ambient high-resolution mass spectrometry (MS) imaging technique of atmospheric pressure-nanoparticle and plasma-assisted laser desorption ionization (AP-nanoPALDI). AP-nanoPALDI analyses of fresh zebrafish caudal fins revealed that the small molecules, including neurotransmitters, amino acids, lipids, and metabolites of the regenerated area, were more evenly distributed throughout the bony rays and inter-ray mesenchymal tissues compared to the original area in the early stage. Zebrafish caudal fins of less than 200 µm thickness can be very useful for tissue regeneration studies using ambient MS imaging by providing sufficient biomolecular information at the molecular level for wound-healing studies. AP-nanoPALDI imaging was compared with a complementary MS imaging tool, surface sensitive time-of-flight secondary ion MS (ToF-SIMS).

The adverse role of excess negative ions in reducing the photoluminescence from water soluble MAA-CdSe/ZnS quantum dots in various phosphate buffers.

The use of CdSe/ZnS quantum dots in making biosensors or biomarkers requires them to be water soluble, which can be achieved by conjugating with MAA. We report observation of modulation in the photoluminescence intensities of MAA conjugated CdSe/ZnS QDs (MAA-QDs) that depended strongly on the types and quantity of negative ions present in various kinds of phosphate buffers. The deterioration of PL was attributed to the presence of excess ions in the media that altered the energy and occupation of HOMO and LUMO levels of MAA. Instantaneously, strong reduction in the PL intensity with pH was observed. MAA-QDs incubated for more than 24 hours in the phosphate buffer at pH ∼ 7.0-8.0 showed recovery and enhanced PL intensity, which was attributed to the presence of excess positive ions and a small amount of OH-. Saline buffers showed no significant recovery due to the presence of additional Cl- ions. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) measurements were successfully employed to determine the band edges of the MAA-QD system in the presence of excess positive or negative ions (Na+, H+, Cl-, and OH-) in the media. Thus, it is very important to have complete knowledge of the ions present in the buffer when using MAA-QDs for biomarking or biosensing applications.

Ultrafast and Efficient Transport of Hot Plasmonic Electrons by Graphene for Pt Free, Highly Efficient Visible-Light Responsive Photocatalyst.

We report that reduced graphene-coated gold nanoparticles (r-GO-AuNPs) are excellent visible-light-responsive photocatalysts for the photoconversion of CO2 into formic acid (HCOOH). The wavelength-dependent quantum and chemical yields of HCOOH shows a significant contribution of plasmon-induced hot electrons for CO2 photoconversion. Furthermore, the presence and reduced state of the graphene layers are critical parameters for the efficient CO2 photoconversion because of the electron mobility of graphene. With an excellent selectivity toward HCOOH (>90%), the quantum yield of HCOOH using r-GO-AuNPs is 1.52%, superior to that of Pt-coated AuNPs (quantum yield: 1.14%). This indicates that r-GO is a viable alternative to platinum metal. The excellent colloidal stability and photocatalytic stability of r-GO-AuNPs enables CO2 photoconversion under more desirable reaction conditions. These results highlight the role of reduced graphene layers as highly efficient electron acceptors and transporters to facilitate the use of hot electrons for plasmonic photocatalysts. The femtosecond transient spectroscopic analysis also shows 8.7 times higher transport efficiency of hot plasmonic electrons in r-GO-AuNPs compared with AuNPs.

Combined Positron Emission Tomography and Cerenkov Luminescence Imaging of Sentinel Lymph Nodes Using PEGylated Radionuclide-Embedded Gold Nanoparticles.

New imaging probes with high sensitivity and stability are urgently needed to accurately detect sentinel lymph nodes (SLNs) for successful cancer diagnosis. Herein, the use of highly sensitive and stable PEGylated radionuclide-embedded gold nanoparticles (PEG-RIe-AuNPs) is reported for the detection of SLNs by combined positron emission tomography and Cerenkov luminescence imaging (PET/CLI). PEG-RIe-AuNPs show high sensitivity and stability both in vitro and in vivo, and are not toxic to normal ovarian and immune cells. In vivo PET/CLI imaging clearly reveals SLNs as early as 1 h post PEG-RIe-AuNP-injection, with peak signals achieved at 6 h postinjection, which is consistent with the biodistribution results. Taken together, the data provide strong evidence that PEG-RIe-AuNPs are promising as potential lymphatic tracers in biomedical imaging for pre and intraoperative surgical guidance.

High resolution live cell Raman imaging using subcellular organelle-targeting SERS-sensitive gold nanoparticles with highly narrow intra-nanogap.

We report a method to achieve high speed and high resolution live cell Raman images using small spherical gold nanoparticles with highly narrow intra-nanogap structures responding to NIR excitation (785 nm) and high-speed confocal Raman microscopy. The three different Raman-active molecules placed in the narrow intra-nanogap showed a strong and uniform Raman intensity in solution even under transient exposure time (10 ms) and low input power of incident laser (200 µW), which lead to obtain high-resolution single cell image within 30 s without inducing significant cell damage. The high resolution Raman image showed the distributions of gold nanoparticles for their targeted sites such as cytoplasm, mitochondria, or nucleus. The high speed Raman-based live cell imaging allowed us to monitor rapidly changing cell morphologies during cell death induced by the addition of highly toxic KCN solution to cells. These results strongly suggest that the use of SERS-active nanoparticle can greatly improve the current temporal resolution and image quality of Raman-based cell images enough to obtain the detailed cell dynamics and/or the responses of cells to potential drug molecules.

Thiolated DNA-based chemistry and control in the structure and optical properties of plasmonic nanoparticles with ultrasmall interior nanogap.

The design, synthesis and control of plasmonic nanostructures, especially with ultrasmall plasmonically coupled nanogap (∼1 nm or smaller), are of significant interest and importance in chemistry, nanoscience, materials science, optics and nanobiotechnology. Here, we studied and established the thiolated DNA-based synthetic principles and methods in forming and controlling Au core-nanogap-Au shell structures [Au-nanobridged nanogap particles (Au-NNPs)] with various interior nanogap and Au shell structures. We found that differences in the binding affinities and modes among four different bases to Au core, DNA sequence, DNA grafting density and chemical reagents alter Au shell growth mechanism and interior nanogap-forming process on thiolated DNA-modified Au core. Importantly, poly A or poly C sequence creates a wider interior nanogap with a smoother Au shell, while poly T sequence results in a narrower interstitial interior gap with rougher Au shell, and on the basis of the electromagnetic field calculation and experimental results, we unraveled the relationships between the width of the interior plasmonic nanogap, Au shell structure, electromagnetic field and surface-enhanced Raman scattering. These principles and findings shown in this paper offer the fundamental basis for the thiolated DNA-based chemistry in forming and controlling metal nanostructures with ∼1 nm plasmonic gap and insight in the optical properties of the plasmonic NNPs, and these plasmonic nanogap structures are useful as strong and controllable optical signal-generating nanoprobes.

Enhanced photothermal effect of plasmonic nanoparticles coated with reduced graphene oxide.

We report plasmonic gold nanoshells and nanorods coated with reduced graphene oxide that produce an enhanced photothermal effect when stimulated by near-infrared (NIR) light. Electrostatic interactions between nanosized graphene oxide and gold nanoparticles followed by in situ chemical reduction generated reduced graphene oxide-coated nanoparticles; the coating was demonstrated using Raman and HR-TEM. Reduced graphene oxide-coated gold nanoparticles showed enhanced photothermal effect compared to noncoated or nonreduced graphene oxide-coated gold nanoparticles. Reduced graphene oxide-coated gold nanoparticles killed cells more rapidly than did noncoated or nonreduced graphene oxide-coated gold nanoparticles.

Accurately Controlled Tumor Temperature with Silica-Coated Gold Nanorods for Optimal Immune Checkpoint Blockade Therapy.

Photothermal therapy (PTT) at mild temperatures ranging from 44 to 45 °C holds tremendous promise as a strategy for inducing potent immunogenic cell death (ICD) within tumor tissues, which can reverse the immunosuppressive tumor microenvironment (ITM) into an immune-responsive milieu. However, accurately and precisely controlling the tumor temperature remains a formidable challenge. Here, we report the precision photothermal immunotherapy by using silica-coated gold nanorods (AuNR@SiO2), and investigating the optimal administration routes and treatment protocols, which enabled to achieve the sustained and controlled mild heating within the tumor tissues. First, the highest photothermal performance of AuNR@SiO2 with 20-nm silica shell thickness than 5 or 40 nm was confirmed in vitro and in vivo. Then, the optimal conditions for precision immunotherapy were further investigated to produce mild temperature (44 to 45 °C) accurately in tumor tissues. The optimal conditions with AuNR@SiO2 result in a distinct cell death with high early/late apoptosis and low necrosis, leading to very efficient ICD compared to lower or higher temperatures. In colon tumor-bearing mice, intratumorally injected AuNR@SiO2 efficiently promotes a mild temperature within the tumor tissues by local irradiation of near-infrared (NIR) laser. This mild PTT substantially increases the population of mature dendritic cells (DCs) and cytotoxic T cells (CTLs) within tumor tissues, ultimately reversing the ITM into an immune-responsive milieu. Furthermore, we found that the combination mild PTT with AuNR@SiO2 and anti-PD-L1 therapy could lead to the 100% complete regression of primary tumors and immunological memory to prevent tumor recurrence. Collectively, this study demonstrates that AuNR@SiO2 with a robust methodology capable of continuously inducing mild temperature accurately within the ITM holds promise as an approach to achieve the precision photothermal immunotherapy.

Photothermal Effect of Gold Nanoparticles as a Nanomedicine for Diagnosis and Therapeutics.

Gold nanoparticles (AuNPs) have received great attention for various medical applications due to their unique physicochemical properties. AuNPs with tunable optical properties in the visible and near-infrared regions have been utilized in a variety of applications such as in vitro diagnostics, in vivo imaging, and therapeutics. Among the applications, this review will pay more attention to recent developments in diagnostic and therapeutic applications based on the photothermal (PT) effect of AuNPs. In particular, the PT effect of AuNPs has played an important role in medical applications utilizing light, such as photoacoustic imaging, photon polymerase chain reaction (PCR), and hyperthermia therapy. First, we discuss the fundamentals of the optical properties in detail to understand the background of the PT effect of AuNPs. For diagnostic applications, the ability of AuNPs to efficiently convert absorbed light energy into heat to generate enhanced acoustic waves can lead to significant enhancements in photoacoustic signal intensity. Integration of the PT effect of AuNPs with PCR may open new opportunities for technological innovation called photonic PCR, where light is used to enable fast and accurate temperature cycling for DNA amplification. Additionally, beyond the existing thermotherapy of AuNPs, the PT effect of AuNPs can be further applied to cancer immunotherapy. Controlled PT damage to cancer cells triggers an immune response, which is useful for obtaining better outcomes in combination with immune checkpoint inhibitors or vaccines. Therefore, this review examines applications to nanomedicine based on the PT effect among the unique optical properties of AuNPs, understands the basic principles, the advantages and disadvantages of each technology, and understands the importance of a multidisciplinary approach. Based on this, it is expected that it will help understand the current status and development direction of new nanoparticle-based disease diagnosis methods and treatment methods, and we hope that it will inspire the development of new innovative technologies.

Nano-Biotechnology for Bacteria Identification and Potent Anti-bacterial Properties: A Review of Current State of the Art.

Sepsis is a critical disease caused by the abrupt increase of bacteria in human blood, which subsequently causes a cytokine storm. Early identification of bacteria is critical to treating a patient with proper antibiotics to avoid sepsis. However, conventional culture-based identification takes a long time. Polymerase chain reaction (PCR) is not so successful because of the complexity and similarity in the genome sequence of some bacterial species, making it difficult to design primers and thus less suitable for rapid bacterial identification. To address these issues, several new technologies have been developed. Recent advances in nanotechnology have shown great potential for fast and accurate bacterial identification. The most promising strategy in nanotechnology involves the use of nanoparticles, which has led to the advancement of highly specific and sensitive biosensors capable of detecting and identifying bacteria even at low concentrations in very little time. The primary drawback of conventional antibiotics is the potential for antimicrobial resistance, which can lead to the development of superbacteria, making them difficult to treat. The incorporation of diverse nanomaterials and designs of nanomaterials has been utilized to kill bacteria efficiently. Nanomaterials with distinct physicochemical properties, such as optical and magnetic properties, including plasmonic and magnetic nanoparticles, have been extensively studied for their potential to efficiently kill bacteria. In this review, we are emphasizing the recent advances in nano-biotechnologies for bacterial identification and anti-bacterial properties. The basic principles of new technologies, as well as their future challenges, have been discussed.

Recent Studies and Progress in the Intratumoral Administration of Nano-Sized Drug Delivery Systems.

Over the last 30 years, diverse types of nano-sized drug delivery systems (nanoDDSs) have been intensively explored for cancer therapy, exploiting their passive tumor targetability with an enhanced permeability and retention effect. However, their systemic administration has aroused some unavoidable complications, including insufficient tumor-targeting efficiency, side effects due to their undesirable biodistribution, and carrier-associated toxicity. In this review, the recent studies and advancements in intratumoral nanoDDS administration are generally summarized. After identifying the factors to be considered to enhance the therapeutic efficacy of intratumoral nanoDDS administration, the experimental results on the application of intratumoral nanoDDS administration to various types of cancer therapies are discussed. Subsequently, the reports on clinical studies of intratumoral nanoDDS administration are addressed in short. Intratumoral nanoDDS administration is proven with its versatility to enhance the tumor-specific accumulation and retention of therapeutic agents for various therapeutic modalities. Specifically, it can improve the efficacy of therapeutic agents with poor bioavailability by increasing their intratumoral concentration, while minimizing the side effect of highly toxic agents by restricting their delivery to normal tissues. Intratumoral administration of nanoDDS is considered to expand its application area due to its potent ability to improve therapeutic effects and relieve the systemic toxicities of nanoDDSs.