Properties Of Nanomedicines Research Articles

Artificial Intelligence: A Catalyst for Breakthroughs in Nanotechnology and Pharmaceutical Research

Artificial intelligence (AI) is revolutionizing nanotechnology and pharmaceutical research by streamlining drug discovery, optimizing formulations, and personalizing treatments through predictive modelling and data analysis. Without AI, the pharmaceutical industry requires more time due to less effective drug discovery, inefficient clinical trials, and prolonged regulatory processes, resulting in higher costs and delayed treatments1. The integration of AI with nanotechnology and pharmaceutical science is revolutionizing medicine, opening up new possibilities for diagnosis, treatment, and personalized healthcare. It also enhances clinical treatments and identifies new uses for existing drugs, reducing development time and costs2. By leveraging machine learning algorithms, researchers can predict the properties and behaviour of nanomaterials, facilitating the development of nanoparticles that can deliver drugs more efficiently to specific cells or tissues3. AI accelerates nano product development by optimizing nanomaterial design, predicting nanoparticle toxicity, and enhancing nanomedicine formulation. For example, AI has been used to design nanoparticles for targeted drug delivery, improving their efficiency and safety4. AI-enabled nanotechnology can enhance molecular profiling and early diagnosis, refine the design of nanomedicines, and improve their efficacy. By optimizing nanomedicine properties, achieving effective drug synergy, and reducing nanotoxicity, AI facilitates better targetability and accelerates the development of personalized treatments.

Manipulation of protein corona for nanomedicines.

Nanomedicines have significantly advanced the development of diagnostic and therapeutic strategies for various diseases, while they still encounter numerous challenges. Upon entry into the human body, nanomedicines interact with biomolecules to form a layer of proteins, which is defined as the protein corona that influences the biological properties of nanomedicines. Traditional approaches have primarily focused on designing stealthy nanomedicines to evade biomolecule adsorption; however, due to the intricacies of the biological environment within body, this method cannot completely prevent biomolecule adsorption. As research on the protein corona progresses, manipulating the protein corona to modulate the in vivo behaviors of nanomedicines has become a research focus. In this review, modern strategies focused on influencing the biological efficacy of nanomedicines in vivo by manipulating protein corona, along with their wide-ranging applications across diverse diseases are critically summarized, highlighted and discussed. Finally, future directions for this important yet challenging research area are also briefly discussed. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.

Triple-transformable dynamic surroundings for programmed transportation of bio-vulnerable mRNA payloads towards systemic treatment of intractable solid tumors

The surface physiochemical properties of nanomedicine play a crucial role in modulating biointerfacial reactions in sequential biological compartments, accordingly accomplishing the desired programmed delivery scenario to intracellular targets. PEGylation, which involves modifying the surface with a layer of poly(ethylene glycol), has been validated as an effective strategy for minimizing adverse biointerfacial interactions. However, it has also been observed to impede cellular uptake and intracellular trafficking activities. To address this dilemma, we propose a dynamic surface chemistry approach that actively prevents non-specific reactions in systemic circulation, while readily facilitating cellular uptake by converting into a highly cytomembrane-adhesive state. Moreover, the surface becomes more adhesive to endolysosomal membranes, enabling translocation into the cytosol. In this study, PEGylated mRNA delivery nanoparticulates were tethered with charge-reversible polymers to create dynamic surroundings through click chemistry. Importantly, the dynamic surroundings exhibited negative charges under physiological conditions (pH 7.4). This property prevented degradation by anionic nucleases and structural disassembly induced by endogenous charged biological species. Consequently, the nanoparticles exhibited appreciable stealth function, effectively managing the first pass effect, leading to prolonged blood retention and improved bioavailabilities at targeted cells. Furthermore, the dynamic surroundings shifted towards relatively positive charges in the tumor microenvironment (pH 6.8). As a result, the nanoparticles were more likely to be taken up by tumors due to their electrostatic affinities towards polyanionic cytomembranes. Eventually, the internalized mRNA nanomedicine transformed responsive to the surrounding microenvironment into highly positive charges within acidic endolysosomes (pH 5.0), exerting explosive disruptive potencies on the endolysosomal structures, thus facilitating translocation of mRNA from the digestive endolysosomes into the targeted cytosol. Notably, the dynamic surroundings also reduced the immunogenicity of naked mRNA due to their stealthy properties and rapid endolysosomal translocation functions. In summary, our proposed unique triple-transformable dynamic surface chemistry provided an intriguing delivery scenario that overcomes sequential biological barriers, contributing to efficient expression of the encapsulated mRNA at targeted tumors.

Synthesis and nanoparticle characterization of an Ayurveda formulation Tridhathu Garbha Pottali

Abstract BACKGROUND: The Tridhaatu Garbha Pottali (TGP) Rasayana is a formulation that may not be widely known, but it is prepared using the Gandhaka Drava Paka method of Pottali preparation. It has been reportedly used in the treatment of various conditions, including Putimeha (Pyorrhea), Pradara (Leukorrhea), and Shukra Dosha (seminal abnormalities). Despite its potential benefits, no current research is being conducted on the synthesis and characterization of this formulation. An attempt was made to standardize the method of preparation of TGP Rasayana as mentioned in Rasayogasagar (a classical text of Rasashastra), and nanoparticle (NP) characterization was carried out alongside classical and physicochemical parameters. Presesent study aimed to standardize TGP Rasayana preparation method and analyze for Nanoparticle Characterization. METHODS: TGP Rasayana is a Pottali Rasayana prepared using the Gandhaka Paaka technique, amalgamating Shuddha Parada, Shuddha Swarna, Shuddha Gandhaka, along with Bhasmas of Naga, Vanga, and Yashadha. Swarna-Parada Dhatu Pishti (fusion) was prepared first, followed by the addition of Gandhaka. Then, the Bhasmas of Naga, Vanga, and Yashada were added, well mixed using trituration method, and Kumari Swarasa Bhavana was administered. The resulting TGP Kajjali was given a conical shape and dried, and Pottali was wrapped in four-folded silk material with Gandhaka in between. Pottali Paka was performed in Mritpatra using the Gandhaka Paaka method, placing it in a Valuka Yantra and subjecting it to Mridvagni for 8 h to obtain all Pottali Siddha Lakshana. Then, the obtained TGP Rasayana was analyzed for classical and instrumental parameters, physicochemical parameters, and sophisticated instrumental analyses such as X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray (EDX), Fourier transform infrared spectroscopy (FTIR), and Raman spectra. RESULTS: TGP possessed all classical parameters of Pottali. XRD confirms the presence of HgS, PbS, SnO2, and ZnO. SEM images show the agglomerated appearance of TGP particles. Energy dispersive X-ray analysis (EDAX) confirms the presence of sulfur, zinc, tin, mercury, and lead as major elements, with gold as minor elements. FTIR shows the presence of organic sulphate, aliphatic amines, and alkyl halides. CONCLUSION: The TGP Rasayana that has been prepared contains various NPs that possess functional groups, thus making it a highly effective therapeutic medicine with the properties of nanomedicine.

Studying the stability of polymer nanoparticles by size exclusion chromatography of radioactive polymers

The properties of nanomedicines will influence how they can deliver drugs to patients reproducibly and effectively. For conventional pharmaceutical products, Chemistry, Manufacturing and Control (CMC) documents require monitoring stability and storage conditions. For nanomedicines, studying these important considerations is hindered by a lack of appropriate methods. In this paper, we show how combining radiolabelling with size exclusion chromatography, using a method called SERP (for Size Exclusion of Radioactive Polymers), can inform on the in vitro degradation of polymer nanoparticles. Using nanoparticles composed of biodegradable poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA), we show that SERP is more sensitive than dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) to detect degradation. We also demonstrate that the properties of the polymer composition and the nature of the aqueous buffer affect nanoparticle degradation. Importantly, we show that minute changes in stability that cannot be detected by DLS and NTA impact the pharmacokinetic of nanoparticles injected in vivo. We believe that SERP might prove a valuable method to document and understand the pharmaceutical quality of polymer nanoparticles.

Reduced Macrophage Uptake of Nanoparticles through Surface Modification of Polypeptides with Valine Residues†

Comprehensive SummaryThe structural and surface properties of nanomedicines play an important role in determining their biological fate. Surface chemistry of nanomedicines is one of the key parameters, where researchers used various strategies such as PEGylation to avoid the undesired clearance of nanoparticles (NPs) for enhanced targeting effect. Nevertheless, the fine‐tuning of surface chemistry through polymer functionalization remains largely unexplored. In this concise report, we find that the incorporation of only 10 mol% valine residues into the surface‐anchored poly(L‐glutamic acid) significantly lowered the macrophage uptake of NPs. The introduction of other hydrophobic amino acid residues, however, increased the NPs internalization instead. The chirality and the side‐chain structure of valine played an important role in the unexpected uptake behavior. We believe this work highlights the impact of slight changes of the surface‐anchored polymer structure on the behavior of NPs, drawing people's attention to the careful design of surface chemistry to optimize the nanomedicine design.

Multi-Enzyme Co-Expressed Nanomedicine for Anti-Metastasis Tumor Therapy by Up-Regulating Cellular Oxidative Stress and Depleting Cholesterol.

Tumor cells movement and migration are inseparable from the integrity of lipid rafts and the formation of lamellipodia, and lipid rafts are also a prerequisite for the formation of lamellipodia. Therefore, destroying the lipid rafts is an effective strategy to inhibit tumor metastasis. Herein, a multi-enzyme co-expressed nanomedicine: cholesterol oxidase (CHO) loaded Co─PN3 single-atom nanozyme (Co─PN3 SA/CHO) that can up-regulate cellular oxidative stress, disrupt the integrity of lipid rafts, and inhibit lamellipodia formation to induce anti-metastasis tumor therapy, is developed. In this process, Co─PN3 SA can catalyze oxygen (O2 )and hydrogen peroxide (H2 O2 ) to generate reactive oxygen species (ROS) via oxidase-like and Fenton-like properties. The doping of P atoms optimizes the adsorption process of the intermediate at the active site and enhances the ROS generation properties of nanomedicine. Meantime, O2 produced by catalase-like catalysis can combine with excess cholesterol to generate more H2 O2 under CHO catalysis, achieving enhanced oxidative damage to tumor cells. Most importantly, cholesterol depletion in tumor cells also disrupts the integrity of lipid rafts and inhibits the formation of lamellipodia, greatly inhibiting the proliferation and metastasis of tumor cells. This strategy by up-regulating cellular oxidative stress and depleting cellular cholesterol constructs a new idea for anti-metastasis-oriented cancer therapy strategies.

Regulating Size and Charge of Liposomes in Microneedles to Enhance Intracellular Drug Delivery Efficiency in Skin for Psoriasis Therapy.

The stratum corneum (SC) and cell membrane are two major barriers that hinder the therapeutic outcomes of transdermal drug delivery for the treatment of skin diseases. While microneedles (MNs) can efficiently penetrate the SC to deliver nanomedicines, the optimization of physicochemical properties of nanomedicines in MNs to enhance their in vivo cellular delivery efficiency remains unclear. Here, how the size and surface charge of drug-loaded liposomes in MNs influence the retention time and cellular delivery in psoriatic skin is systematically investigated. The results indicate that while 100nm negatively-charged liposomes in MNs show higher cellular uptake in vitro, 250 and 450nm liposomes could enhance skin retention and the long-term in vivo cellular delivery efficiency of drugs. Moreover, 250nm cationic liposomes with a stronger positive charge show an extraordinarily long skin retention time of 132h and significantly higher in vivo cellular internalization. In the treatment study, dexamethasone (dex)-loaded cationic liposomes-integrated MNs show better therapeutic outcomes than dex-loaded anionic liposomes-integrated MNs in a psoriasis-like animal model. The design principles of liposomes in MN drug delivery systems explored in the study hold the potential for enhancing the therapeutic outcomes of psoriasis and are instrumental for successful translation.

Size Control and Biological Properties of PAMAM-Cored Multiarm Block Copolymers.

Size is one of the crucial factors influencing the biological properties of nanomedicines. However, the size control of nanomaterials is still very challenging, and the size effect on their biological properties is worth studying. Herein, we present the synthesis and size control of a series of multiarm block copolymers with the third-generation PAMAM (G3 PAMAM) as the core. The multiarm copolymers were synthesized by the ring-opening polymerization of N-carboxyanhydride of the l-glutamic acid-5-tert-butylester [Glu(OtBu)-NCA] monomer with the amine-terminated PAMAM as the initiator, followed by the synthesis of the poly(carboxybetaine) (PCB) block via the atom transfer radical polymerization of the 2-(dimethylamino)ethyl methacrylate monomer, the reaction with tert-butyl bromoacetate, and the deprotection of the tert-butyl ester groups. The polyglutamic acid (PGA) block provided abundant reactive groups for the functionalization of the multiarm block copolymers, and the PCB block imparted excellent water solubility and anti-protein adsorption capability. We synthesized three multiarm copolymers with diameters of 15, 24, and 41 nm, respectively, by tuning the polymerization degrees of the arms. Doxorubicin was coupled to the PGA block through the acylhydrazone linkage, which resulted in a pH-sensitive drug release and a drug loading of over 20%. We systematically investigated the size effects on their cellular uptake, cytotoxicity, endocytic pathway, biodistribution, tumor penetration, and antitumor activity. This work is helpful for the design of polymeric nano-drug carriers for tumor therapy.

Fluorination Effects on the Drug Delivery Property of Cylindrical Polymer Brushes.

Fluorination has been widely applied to improving the properties of small-molecule drugs. However, relatively little is known about the effects of fluorination on the drug delivery property of nanomaterials. In this paper, we synthesized a fluoroalkane-modified cylindrical polymer brush (CPB) BCPB-F and an alkane-modified analogue BCPB-H. Doxorubicin (DOX) was used as a model drug and was loaded onto the CPBs through a pH-responsive acylhydrazone linkage. High drug loading and good water solubility were achieved. The in vitro and in vivo experiments suggested that fluorination played an important role in improving the cellular uptake, blood circulation, tissue permeability, and tumor targeting ability of CPBs. Due to these superiorities, the DOX-loaded BCPB-F exhibited excellent antitumor efficacy and eradicated the tumors of mice after five-dose treatments. The well-defined structures of the drug-free and drug-loaded CPBs guaranteed the accuracy of the results. This work demonstrates that fluorination is a promising strategy to improve the overall properties of nanomedicines.

Covalent organic framework nanomedicines: Biocompatibility for advanced nanocarriers and cancer theranostics applications.

Nanomedicines for drug delivery and imaging-guided cancer therapy is a rapidly growing research area. The unique properties of nanomedicines have a massive potential in solving longstanding challenges of existing cancer drugs, such as poor localization at the tumor site, high drug doses and toxicity, recurrence, and poor immune response. However, inadequate biocompatibility restricts their potential in clinical translation. Therefore, advanced nanomaterials with high biocompatibility and enhanced therapeutic efficiency are highly desired to fast-track the clinical translation of nanomedicines. Intrinsic properties of nanoscale covalent organic frameworks (nCOFs), such as suitable size, modular pore geometry and porosity, and straightforward post-synthetic modification via simple organic transformations, make them incredibly attractive for future nanomedicines. The ability of COFs to disintegrate in a slightly acidic tumor microenvironment also gives them a competitive advantage in targeted delivery. This review summarizes recently published applications of COFs in drug delivery, photo-immuno therapy, sonodynamic therapy, photothermal therapy, chemotherapy, pyroptosis, and combination therapy. Herein we mainly focused on modifications of COFs to enhance their biocompatibility, efficacy and potential clinical translation. This review will provide the fundamental knowledge in designing biocompatible nCOFs-based nanomedicines and will help in the rapid development of cancer drug carriers and theranostics.

纳米药物在肿瘤治疗与临床应用的发展与挑战

<p indent="0mm">Nanomedicines are nano-scale drug particles or nano-drug delivery particles formed by carriers and drugs. The small size and large specific surface area of nanomedicine carriers increase drug-loading and <italic>in vivo</italic> circulation time compared with conventional drugs, thus improving efficacy and reducing toxic side effects. This review summarizes the structure, function and biological properties of nanomedicines using liposomes, proteins and carbon quantum-dots <italic>etc</italic>. as carriers, and their clinical application progress in the field of tumor treatment, as well as the significant contribution to the current global pandemic of novel coronavirus pneumonia epidemic. Meanwhile, problems, challenges and prospects of nanomedicines in the clinical application are analyzed. The aim of this review is to provide references for the research and development of nanomedicines in the pharmaceutical field, and also to facilitate the clinical application of nanomedicines.

To PEGylate or not to PEGylate: Immunological properties of nanomedicine's most popular component, polyethylene glycol and its alternatives.

Polyethylene glycol or PEG has a long history of use in medicine. Many conventional formulations utilize PEG as either an active ingredient or an excipient. PEG found its use in biotechnology therapeutics as a tool to slow down drug clearance and shield protein therapeutics from undesirable immunogenicity. Nanotechnology field applies PEG to create stealth drug carriers with prolonged circulation time and decreased recognition and clearance by the mononuclear phagocyte system (MPS). Most nanomedicines approved for clinical use and experimental nanotherapeutics contain PEG. Among the most recent successful examples are two mRNA-based COVID-19 vaccines that are delivered by PEGylated lipid nanoparticles. The breadth of PEG use in a wide variety of over the counter (OTC) medications as well as in drug products and vaccines stimulated research which uncovered that PEG is not as immunologically inert as it was initially expected. Herein, we review the current understanding of PEG's immunological properties and discuss them in the context of synthesis, biodistribution, safety, efficacy, and characterization of PEGylated nanomedicines. We also review the current knowledge about immunological compatibility of other polymers that are being actively investigated as PEG alternatives.

Phenylboronic Acid Modification Augments the Lysosome Escape and Antitumor Efficacy of a Cylindrical Polymer Brush-Based Prodrug.

Timely lysosome escape is of paramount importance for endocytosed nanomedicines to avoid premature degradation under the acidic and hydrolytic conditions in lysosomes. Herein, we report an exciting finding that phenylboronic acid (PBA) modification can greatly facilitate the lysosome escape of cylindrical polymer brushes (CPBs). On the basis of our experimental results, we speculate that the mechanism is associated with the specific interactions of the PBA groups with lysosomal membrane proteins and hot shock proteins. The featured advantage of the PBA modification over the known lysosome escape strategies is that it does not cause significant adverse effects on the properties of the CPBs; on the contrary, it enhances remarkably their tumor accumulation and penetration. Furthermore, doxorubicin was conjugated to the PBA-modified CPBs with a drug loading content larger than 20%. This CPBs-based prodrug could eradicate the tumors established in mice by multiple intravenous administrations. This work provides a novel strategy for facilitating the lysosome escape of nanomaterials and demonstrates that PBA modification is an effective way to improve the overall properties of nanomedicines including the tumor therapeutic efficacy.

Nanomedicine Strategies to Circumvent Intratumor Extracellular Matrix Barriers for Cancer Therapy.

The dense and heterogeneous physical network of the extracellular matrix (ECM) in tumors represents a formidable barrier that limits intratumor drug delivery and the therapeutic efficacy of many anticancer therapies. Here, the two major nanomedicine strategies to circumvent intratumor ECM barriers: regulating the physiochemical properties of nanomedicines and remodeling the components and structure of the ECM are summarized. Nanomedicines can be rationally regulated by optimizing physiochemical properties or designed with biomimetic features to promote ECM permeation capability. Meanwhile, they can also be designed to remodel the ECM by modulating signaling pathways or destroying the components and architecture of the ECM via chemical, biological, or physical treatments. These efforts produce profound improvements in intratumor drug delivery and anticancer efficacy. Moreover, to aid in their anticancer efficacy, feasible approaches for improving ECM-circumventing nanomedicines are proposed.

Convenient Tuning of the Elasticity of Self-Assembled Nano-Sized Triterpenoids to Regulate Their Biological Activities

The impact of the mechanical properties of nanomedicines on their biological functions remains elusive due to the difficulty in tuning the elasticity of the vehicles without changing chemistry. Herein, we report the fabrication of elasticity-tunable self-assembled oleanolic acid (OA) nanoconstructs in an antiparallel zigzag manner and develop rigid nanoparticles (OA-NP) and flexible nanogels (OA-NG) as model systems to decipher the elasticity-biofunction relationship. OA-NG demonstrate less endocytosis and enhanced lysosome escape with deformation compared to OA-NP. Further in vitro and in vivo experiments show the active permeation of OA-NG into the interior of tumor with enhanced antitumor efficacy accompanied by decreased collagen production and eight- to tenfold immune cell infiltration. This study not only presents a facile and green strategy to develop flexible OA-NG for effective cancer treatment but also uncovers the crucial role of elasticity in regulating biological activity, which may provide reference for precise design of efficient nanomedicines.

Theranostics: A Boon in Cancer Diagnosis and Therapy

Modern approaches in improvement of new nanomaterials have gained enormous attention due to various biomedical application, along with cancer theranostics. The characteristic physico-chemical feature of these materials, including their small size and wide-range surface-to-volume ratio provide potentiality for cancer theranostics that combine diagnosis , biosensing , imaging detection and immune therapy.Recent procurement for cancer immunotherapy have gained considerable attention in controlling the body’s immune system to fight against cancer.In this abstract , nanomedicine with inherent immunomodulatory properties presents interesting window(of opportunity) which can stimulate the function of immune cell. The goal is to cover broad range of information about the immunomodulation properties of nanomedicine in cancer theranostics i.e factors like pH, hypoxia, tumor angiogenesis, tumor extracellular matrix which have a huge role in the immunomodulation of nanomedicine and also strategies to enhance cancer theranostics applications. According to recent studies, cancer therapy can be potentially improved through nanoparticle based immunotherapy.

In Vitro and In Vivo Models for Evaluating the Oral Toxicity of Nanomedicines.

Toxicity studies for conventional oral drug formulations are standardized and well documented, as required by the guidelines of administrative agencies such as the US Food & Drug Administration (FDA), the European Medicines Agency (EMA) or European Medicines Evaluation Agency (EMEA), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Researchers tend to extrapolate these standardized protocols to evaluate nanoformulations (NFs) because standard nanotoxicity protocols are still lacking in nonclinical studies for testing orally delivered NFs. However, such strategies have generated many inconsistent results because they do not account for the specific physicochemical properties of nanomedicines. Due to their tiny size, accumulated surface charge and tension, sizeable surface-area-to-volume ratio, and high chemical/structural complexity, orally delivered NFs may generate severe topical toxicities to the gastrointestinal tract and metabolic organs, including the liver and kidney. Such toxicities involve immune responses that reflect different mechanisms than those triggered by conventional formulations. Herein, we briefly analyze the potential oral toxicity mechanisms of NFs and describe recently reported in vitro and in vivo models that attempt to address the specific oral toxicity of nanomedicines. We also discuss approaches that may be used to develop nontoxic NFs for oral drug delivery.

Surface-Engineered Cancer Nanomedicine: Rational Design and Recent Progress.

Cancer is highly heterogeneous in nature and characterized by abnormal, uncontrolled cells' growth. It is responsible for the second leading cause of death in the world. Nanotechnology is explored profoundly for sitespecific delivery of cancer chemotherapeutics as well as overcome multidrug-resistance (MDR) challenges in cancer. The progress in the design of various smart biocompatible materials (such as polymers, lipids and inorganic materials) has now revolutionized the area of cancer research for the rational design of nanomedicine by surface engineering with targeting ligands. The small tunable size and surface properties of nanomedicines provide the opportunity of multiple payloads and multivalent-ligand targeting to achieve drug efficacy even in MDR cancer. Furthermore, efforts are being carried out for the development of novel nano-pharmaceutical design, focusing on the delivery of therapeutic and diagnostic agents simultaneously which is called theranostics to assess the progress of therapy in cancer. This review aimed to discuss the physicochemical manipulation of cancer nanomedicine for rational design and recent progress in the area of surface engineering of nanomedicines to improve the efficacy of cancer chemotherapeutics in MDR cancer as well. Moreover, the problem of toxicity of the advanced functional materials that are used in nanomedicines and are exploited to achieve drug targeting in cancer is also addressed.

Potential drug delivery nanosystems for improving tumor penetration

Nanosystems, as one of the most important drug delivery systems, play a crucial rule in tumor therapy. However, the deep tumor penetration is retarded by the tumor physiological factors and nanomedicine properties. In this review, we firstly elaborate the factors which impact tumor penetration, including the tumor physiological factors and nanomedicine properties. Then, the latest and potential drug delivery nanosystems for improving tumor penetration are summarized and analyzed in detail. Moreover, recent combination therapies for improving penetration are described to enhance penetration. Finally, we summarize the typical clinical therapies of potential drug delivery nanosystems.