Glioblastoma (GBM), the most common primary brain tumor, lacks effective treatments. Emerging evidence suggests mitochondria as a promising therapeutic target, albeit successfully targeting represents a major challenge. Recently, we discovered a group of triterpenes that can self-assemble into nanoparticles (NPs) for cancer treatment. However, unmodified triterpene NPs lack affinity for mitochondria. In this study, using oleanolic acid (OA) as an example, we demonstrated that tertiary amine modification enabled triterpene NPs to selectively target the mitochondria through interaction with translocase of outer mitochondrial membrane 70 (TOM70) leading to effective killing of GBM cells via pyroptosis. We showed that the NPs could be engineered for preferentially penetrating brain tumors through surface conjugation of iRGD, and treatment with the resulting NPs significantly prolonged the survival of tumor-bearing mice. We found that the efficacy could be further improved by encapsulating lonidamine, a mitochondrial hexokinase inhibitor. Furthermore, the observed mitochondria targeting effect through tertiary amine modification could be extended to other triterpenes, including lupeol and glycyrrhetinic acid. Collectively, this study reveals a novel strategy for targeting the mitochondria through tertiary amine modification of triterpenes, offering a promising avenue for the effective treatment of GBM.

Improving the efficacy of gastric cancer (GC) treatment remains an ongoing challenge. Considering the increasing importance of PANoptosis, a novel form of programmed cell death, the current study integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) into nanoliposomes. This approach utilizes the ability of photosensitizer Chlorin e6 (Ce6) to generate reactive oxygen species (ROS) and the function of the natural targeting agent Jolkinolide B to activate the PANoptosis molecular switch, inducing the ROS-caspase8/PANoptosis pathway to promote GC cell death. The designed CJP-TiN liposome targets GC via internalizing RGD peptide (iRGD), and demonstrates ROS/pH dual responsiveness in the tumor microenvironment. In vitro and in vivo experiments show effective ROS generation ability under light exposure, killing tumor cells and triggers thioether bond cleavage for dual-controlled drug release. The combined therapy enhances antitumor effect, converting "cold tumors" into "hot tumors," thereby enhancing the success of immunotherapy. The role of CJP-TiN as a PANoptosis inducer in the tumor microenvironment is confirmed, thereby expanding its application potential as a molecularly targeted therapy for GC treatment, and providing a novel perspective for therapeutic strategies.

Camptothesome, a sphingomyelin (SM)-conjugated camptothecin (CPT) vesicular nanotherapeutic, addresses the poor solubility and lactone instability of CPT while enhancing drug loading, pharmacokinetics, and tumor distribution compared to CPT physically entrapped in conventional liposomes. Despite these improvements, the tumor uptake remains limited. To further enhance the tumor delivery efficiency and minimize the off-target distribution, we functionalize Camptothesome with the LinTT1 peptide, a CendR motif, which binds to overexpressed p32 proteins on tumor cell surface, initiating effective transcytosis for deep tumor penetration. Via systematic screening, the optimal peptide ratio on Camptothesome is identified. LinTT1/Camptothesome significantly increases cancer cell uptake without affecting normal cell internalization, resulting in enhanced anti-colorectal cancer cells activity. Additionally, decorating Camptothesome with the LinTT1 cell-penetrating peptide enables effective transcytosis via a Golgi-dependent intracellular trafficking mechanism, significantly improving the intratumoral delivery while reducing distribution to normal tissues. In a human HCT116 xenograft colorectal cancer (CRC) mouse model, LinTT1/Camptothesome demonstrates superior antitumor efficacy compared to both Camptothesome and Onivyde by upregulating cleaved caspase-3 and γH2AX. Our study substantiates the potential of leveraging a tumor-penetrating peptide to enhance the tumor delivery efficiency of Camptothesome, maximizing its therapeutic index for improved treatment of human CRC. STATEMENT OF SIGNIFICANCE: Despite the improved tumor delivery achieved by Camptothesome, its tumor distribution and penetration remain limited. This is because the enhanced permeability and retention effect only facilitates nanotherapeutic distribution to tumor periphery through leaky vasculature. The C-end Rule (CendR) motif-neuropilin receptor system enhances tumor-homing peptides by binding to cellular surface receptors, triggering transcytosis. Herein, LinTT1, the most potent CendR peptide that binds to the overexpressed p32 receptor on cancer cells, was effectively engineered onto Camptothesome using thiol-maleimide lipid chemistry. The LinTT1/Camptothesome significantly enhanced tumor uptake and penetration while minimizing accumulation in normal tissues, demonstrating remarkable anticancer efficacy in a human xenograft colorectal cancer model. Our findings highlight the critical role of tumor-homing peptides in unlocking the full therapeutic potential of Camptothesome.

In vivo phage display is a method used for identification of organ- or disease-specific vascular homing peptides for targeted delivery of pharmaceutics. It is agnostic as to the nature and identity of the target molecules. The current in vivo biopanning lacks inbuilt mechanisms to select for peptides capable of vascular homing that would also be capable of tissue penetration to reach therapeutically relevant cells in the tissue parenchyma. Here, we combined in vivo phage display with microdialysis-based parenchymal recovery and high-throughput sequencing to select for peptides that, besides vascular homing, facilitate extravasation and tissue penetration. We first demonstrated in skin wounds that the method can selectively separate known homing peptides from those with additional tissue-penetrating ability. Screening of a naïve peptide library identifies peptides that home and extravasate to extravascular granulation tissue in vascularized and diabetic wounds and cross blood-retina barrier in retinopathy. Our work suggests that in vivo phage display combined with microdialysis can be used for the discovery of vascular homing peptides capable of extravasation and tissue penetration.

In immunotherapy, peptide-based medications are showing great promise as a new class of therapies that can be used to treat autoimmune diseases, cancer, and other immune-related conditions. Peptides are being created for use in immunotherapy as vaccines, immunological modulators, and adjuvants because of their capacity to precisely alter immune responses. They can imitate endogenous signals or interact with immune cells, improving the body's capacity to identify and combat malignancies or reestablishing immunological tolerance in autoimmune disorders. Notably, peptide-based treatments have demonstrated promise in promoting tumor-specific immune responses and improving the effectiveness of already available immunotherapies, such as immune checkpoint inhibitors. Notwithstanding its potential, peptide-based medications' clinical translation is fraught with difficulties, such as those pertaining to immunogenicity, bioavailability, and peptide stability. Overcoming these obstacles has been made possible by developments in peptide engineering, including pharmacokinetic optimization, receptor-binding affinity enhancement, and the creation of innovative delivery systems. The targeted distribution and effectiveness of peptide medications can be improved by using liposomes, nanoparticles, and other delivery methods, increasing their therapeutic utility. With an emphasis on recent scientific developments, mechanisms of action, and therapeutic uses, this review examines the present status of peptide-based medications in immunotherapy. We also look at the obstacles that still need to be overcome in order to get peptide-based treatments from the lab to the clinic and offer suggestions for future research initiatives. By tackling these important problems, we hope to demonstrate how peptide-based medications have the ability to revolutionize immunotherapeutic treatment approaches.

Catalytic DNA circuits have emerged as a powerful tool for high-performance biosensing application; however, the establishment of a safe and efficient in vivo delivery system remains a critical bottleneck. Peptides serve as attractive carriers due to their rich chemical diversity, excellent biocompatibility, high loading capacity, and specific binding ability, making them ideal candidates for the on-demand regulation of DNA circuits-yet remains largely unexplored. In this study, we developed a multifunctional enzyme-responsive peptide (ERP) for the efficient loading and specific intracellular delivery and release of catalytic circuitry probes through a phosphorylation-based charge reversal procedure. This ERP-programmed catalytic DNA circuit enables the precise, spatially controllable in vivo imaging of microRNA (miRNA). The multifunctional cationic peptide formed a stable nanocomplex with anionic DNA cargo via strong electrostatic interactions, thus protecting the DNA probes from degradation in biological environments. Moreover, with the ability to actively targeting tumor cells and facilitate endogenous phosphorylation-guided release of DNA probes, this multifunctional peptide could significantly reduce the nonspecific delivery of probes to healthy tissues, thereby minimizing unwanted off-site signal leakage. By the integration of cell-selective delivery and site-specific stimulation, this endogenously regulated and multiply guaranteed DNA circuit system paves a simple yet effective way for disease diagnosis.

Protein-protein interactions (PPIs) regulate essential physiological and pathological processes. Due to their large and shallow binding surfaces, PPIs are often considered challenging drug targets for small molecules. Peptides offer a viable alternative, as they can bind these targets, acting as regulators or mimicking interaction partners. This review focuses on competitive peptides, a class of orthosteric modulators that disrupt PPI formation. We provide a concise yet comprehensive overview of recent advancements in in-silico peptide design, highlighting computational strategies that have improved the efficiency and accuracy of PPI-targeting peptides. Additionally, we examine cutting-edge experimental methods for evaluating PPI-based peptides. By exploring the interplay between computational design and experimental validation, this review presents a structured framework for developing effective peptide therapeutics targeting PPIs in various diseases.

Prostate cancer (PC) contributes to male mortality worldwide. The objective of this study is to comprehensively depict the scientific accomplishments and research trends in nanotechnology for PC applications.

Utilizing the Web of Science Core Collection database, publications were gathered on the basis of inclusion and selection criteria. The publications were analyzed and visualized using VOSviewer, R-studio and CiteSpace software tools.

A total of 1949 studies were incorporated. Farokhzad was the most productive author. The United States and China released 58.13% of the total publications. The Chinese Academy of Sciences was the most influential institution, and the International Journal of Nanomedicine stood out as a prominent journal in this field. The most frequently referenced publication and research subject category were identified. The most extensively investigated area was nanoparticle-based drug delivery, while recent research has focused on anticancer with novel nanocarriers.

A bibliometric analysis in the PC and nanotechnology was conducted between 2004 and 2023. The overview and characteristics of the publications were identified. We discussed the application and restrictions faced by nanotechnology in PC management. The study of nanotechnology in PC treatment needs to be further studied.

It is estimated that between 80 and 90% of mortality in cancer patients is directly or indirectly related to drug resistance. Consequently, overcoming drug resistance represents a significant challenge in the treatment of cancer. Integrins are transmembrane adhesion molecules that facilitate the linkage between the extracellular matrix (ECM) and the cytoskeleton, thereby enabling the activation of various cellular signaling pathways. Integrins are highly expressed in various cancers and contribute to cancer progression through invasion and metastasis. In addition, recent studies have revealed that integrins play a pivotal role in the development of drug resistance in cancer. This review will first provide an overview of integrin function and classification. It then discusses recent advances in understanding how integrins contribute to drug resistance in cancer, with a focus on ECM, drug transporters, the epithelial-to-mesenchymal transition (EMT), cancer stemness, PD-L1, and glycosylation. Finally, the potential applications of integrins as targets for therapeutic agents against drug-resistant cancers are also summarized.

Cyclodextrins (CDs) are cyclic polysaccharides characterized by their unique hollow structure, making them highly effective carriers for pharmaceutical agents. CD-based delivery systems are extensively utilized to enhance drug stability, increase solubility, improve oral bioavailability, and facilitate controlled release and targeted delivery. This review initially provides a concise overview of nano drug delivery systems, followed by a detailed introduction of the structural features and benefits of CDs. It further summarizes the applications of CD-based delivery systems and offers insights for the rational design of drug delivery systems. In this review, CD-based delivery systems are categorized into several types, such as covalently modified CD derivatives, non-modified CD inclusion complexes, poly-cyclodextrins and others. The application of CD-based systems for the delivery of genetic therapeutic agents and co-delivery of gene and drug is also presented. Finally, this review discusses potential challenges and opportunities that may arise in the future. With the development of nanotechnology and optimization of preparation process, CD-based drug delivery systems will provide a more effective, precise and safe approach to drug therapy.

The blood-brain barrier (BBB) impedes the transportation of drugs to the brain, thereby constraining the efficacy of treatments for brain diseases. Here, a pH-sensitive nanocarrier coated with a brain metastatic tumor cell membrane (CA-iRGD-CS@M) is designed to enhance drug delivery across the BBB by simultaneously improving cellular uptake and accelerating lysosomal escape. The cell membrane coating can recognize brain microvessel endothelial cells (BMECs) to improve cellular uptake. The pH-sensitive nanocarrier (CA-iRGD-CS) as the core of CA-iRGD-CS@M undergoes charge reversal triggered by the acidic environment of lysosomes, leading to the disruption of the coated cell membrane and further promoting the escape of the detached core from lysosomes into the brain parenchyma. Facilitated by the targeting ligand iRGD, the detached core containing the photothermal agent (CuS) can target the tumor site and fulfill deep penetration, thereby achieving efficient NIR-II photothermal therapy.

Given the unique capabilities of natural cell membranes, such as prolonged blood circulation and homotypic targeting, extensive research has been devoted to developing cell membrane-inspired nanocarriers for cancer therapy, while most focused on overcoming one or a few biological barriers. In fact, the journey of nanosystems from systemic circulation to tumor cells involves intricate processes, encompassing blood circulation, tissue accumulation, cancer cell targeting, endocytosis, endosomal escape, intracellular trafficking to target sites, and therapeutic action, all of which pose limitations to their clinical translation. This underscores the necessity of meticulously considering these biological barriers in the design of cell membrane-mimetic nanocarriers. In this review, we delineate the functions and applications of diverse types of cell membranes in nanocarrier systems. We elaborate on the biological hurdles encountered at each stage of the biomimetic nanoparticle's odyssey to the target, and comprehensively discuss the obstacles imposed by the tumor microenvironment for precise delivery. Subsequently, we systematically review contemporary cell membrane-based strategies aimed at overcoming these multi-level biological barriers, encompassing hybrid cell membrane (HCM) camouflage, tumor microenvironment remodeling, endosomal/lysosomal escape, multidrug resistance (MDR) reversal, optimization of nanoparticle physicochemical properties, and so on. Finally, we outline potential strategies to accelerate the development of cell membrane-inspired precision nanocarriers and discuss the challenges that must be addressed to enhance their clinical applicability. This review serves as a guide for refining the study of cell membrane-mimetic nanosystems in surmounting in vivo delivery barriers, thereby significantly contributing to advancing the development and application of cell membrane-based nanoparticles in cancer delivery.

Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy.

Integrins are well-characterized receptors involved in cell adhesion and signaling. With six approved drugs, they are recognized as valuable therapeutic targets. Here, we explore potential activation mechanisms that may clarify the agonist versus antagonist behavior of integrin ligands. The reorganization of the transmembrane domain (TMD) in the integrin receptor, forming homooligomers within focal adhesions, could be key to the understanding of the agonistic properties of integrin ligands at substoichiometric concentrations. This has significant implications for medical applications. While we focus on the RGD peptide-recognizing integrin subfamily, we propose that these mechanistic insights may also apply to other integrin subtypes. For application of integrin ligands in medicine it is essential to consider this mechanism and its consequences for affinity and bioavailability.

Certepetide (aka LSTA1 and CEND-1) is a novel cyclic tumor-targeting internalizing arginyl glycylaspartic acid peptide being developed to treat solid tumors. Certepetide is designed to overcome existing challenges in treating solid tumors by delivering co-administered anticancer drugs into the tumor while selectively depleting immunosuppressive T cells, enhancing cytotoxic T cells in the tumor microenvironment, and inhibiting the metastatic cascade. A population pharmacokinetic (PK) analysis was conducted to characterize the concentration-time profile of patients with metastatic exocrine pancreatic cancer receiving certepetide in combination with nab-paclitaxel and gemcitabine, and to investigate the effects of clinically relevant covariates on PK parameters. The PK of certepetide was characterized by a 2-compartment model with linear elimination and a proportional residual error structure. Body weight and baseline creatinine clearance (CrCL) were found to have statistically significant effects on central and peripheral volume (Vc and Vp) and clearance (CL) parameters, respectively, during model development and were included as covariate effects in the final PK model. Forest plots demonstrated a potentially clinically meaningful impact of high body weight (100 kg) on certepetide exposure (steady-state maximum concentration [Cmax,ss] and area under the concentration-time curve [AUCss]), as well as low and high CrCL (50 and 150 mL/min) on AUCss. Exposure predictions illustrated a relationship between certepetide exposure (AUCss) and renal function, with increasing exposure and decreasing CL of certepetide observed with worsening renal function. Modeling will strengthen the understanding of certepetide's PKs and will inform dose optimization in ongoing drug development activities.

More effective drug formulations are needed to increase the selectivity and efficacy of available chemotherapeutics. We have previously shown that nanoparticles decorated with the tumour homing peptide CGKRK can selectively deliver payloads to the placenta. In this study, we investigated whether two novel placental homing peptides NKGLRNK (NKG) and RSGVAKS (RSG) can be utilized to selectively deliver doxorubicin (DOX) to breast cancer cells. Fluorescence microscopy and flow cytometry showed that NKG and RSG bind to and accumulate in MDA-MB-231 and MCF-7 cells in a time-dependent manner, to a similar extent as CGKRK, but accumulate in healthy MCF-10A cells to a much lesser degree. NKG- and RSG-decorated liposomes facilitated equivalent delivery of DOX to MDA-MB-231 and MCF-7 cells, with a comparable efficacy to CGKRK-decorated liposomes. These findings suggest that NKG and RSG represent novel breast tumour-binding sequences that could be utilized to develop more efficacious targeted breast cancer therapies.

Recent developments in biomimetic nanoparticles, specifically carbohydrate polymer-coated cell membrane nanoparticles, have demonstrated considerable promise in treating cancer. These systems improve drug delivery by imitating natural cell actions, enhancing biocompatibility, and decreasing immune clearance. Conventional drug delivery methods frequently face challenges with non-specific dispersal and immune detection, which can hinder their efficiency and safety. These biomimetic nanoparticles improve target specificity, retention times, and therapeutic efficiency by using biological components like chitosan, hyaluronic acid, and alginate. Chitosan-based nanoparticles, which come from polysaccharides found in nature, have self-assembly abilities that make them better drug carriers. Hyaluronic acid helps target tissues more effectively, especially in cancer environments where there are high levels of hyaluronic acid receptors. Alginate-based systems also enhance drug delivery by being biocompatible and degradable, making them ideal choices for advanced therapeutic uses. Moreover, these particles hold potential for overcoming resistance to multiple drugs and boosting the body's immune reaction to tumors through precise delivery and decreased side effects of chemotherapy drugs. This review delves into the possibilities of using carbohydrate polymer-functionalized nanoparticles and their impact on enhancing the efficacy of cancer treatment.

Surface modification of proteins and peptides has emerged as a promising strategy to enhance their therapeutic efficacy and target specificity. This chapter delves into the various techniques employed to modify the surface properties of these biomolecules, including chemical conjugation, site-specific mutagenesis, and peptide synthesis. The focus is on strategies that improve drug delivery to specific target sites, such as tumor cells or inflamed tissues. By modifying surface properties, it is possible to enhance drug stability, reduce immunogenicity, and prolong circulation time. This chapter explores the latest advancements in this field and discusses the potential applications of surface-modified proteins and peptides in the development of novel therapeutic agents.

The high mortality rate associated with metastatic breast cancer presents a significant global challenge. Inherent and chemotherapy-induced DNA damage repair, alongside immunosuppression, drastically contribute to triple-negative breast cancer (TNBC) relapse and metastasis. While poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib show effectiveness against BRCA1-mutant TNBC, they may lead to drug resistance and reduced efficacy due to increased programmed death-ligand 1 (PD-L1) expression. Our study explored the use of polymer-lipid nanoparticles (PLN) loaded with doxorubicin (DOX) and oligomeric hyaluronic acid (oHA), functionalized iRGD-peptide for integrins targeting (iRGD-DOX-oHA-PLN), to prevent TNBC immunosuppression, DNA repair, and metastasis. The results demonstrate that the iRGD-DOX-oHA-PLNs efficiently downregulated single and double-strand DNA repair proteins and enhanced DNA damage while decreasing PD-L1 expression compared to olaparib. Accordingly, iRGD-DOX-oHA-PLN treatment showed significantly higher efficiency in reducing levels of primary tumor growth and numbers of metastases to the lung and liver compared to olaparib in vitro and in vivo in both BRCA1-mutant and wild type TNBC orthotopic xenograft models.

Nanotechnology-based delivery systems have brought a paradigm shift in the management of cancer. However, the main obstacles to nanocarrier-based delivery are their limited circulation duration, excessive immune clearance, inefficiency in interacting effectively in a biological context and overcoming biological barriers. This demands effective engineering of nanocarriers to achieve maximum efficacy. Nanocarriers can be maneuvered with biological components to acquire biological identity for further regulating their biodistribution and cell-to-cell cross-talk. Thus, the integration of synthetic and biological components to deliver therapeutic cargo is called a biohybrid delivery system. These delivery systems possess the advantage of synthetic nanocarriers, such as high drug loading, engineerable surface, reproducibility, adequate communication and immune evasion ability of biological constituents. The biohybrid delivery vectors offer an excellent opportunity to harness the synergistic properties of the best entities of the two worlds for improved therapeutic outputs. The major spotlights of this review are different biological components, synthetic counterparts of biohybrid nanocarriers, recent advances in hybridization techniques, and the design of biohybrid delivery systems for cancer therapy. Moreover, this review provides an overview of biohybrid systems with therapeutic and diagnostic applications. In a nutshell, this article summarizes the advantages and limitations of various biohybrid nano-platforms, their clinical potential and future directions for successful translation in cancer management.

Cancer is a significant global health concern associated with multiple distinct factors, including microbial and viral infections. Numerous studies have elucidated the role of microorganisms, such as Helicobacter pylori (H. pylori), as well as viruses for example human papillomavirus (HPV), hepatitis B virus (HBV), and hepatitis C virus (HCV), in the development of human malignancies. Substantial attention has been focused on the treatment of these microorganism- and virus-associated cancers, with promising outcomes observed in studies employing peptide-based therapies. The current paper provides an overview of microbe- and virus-induced cancers and their underlying molecular mechanisms. We discuss an assortment of peptide-based therapies which are currently being developed, including tumor-targeting peptides and microbial/viral peptide-based vaccines. We describe the major technological advancements that have been made in the design, screening, and delivery of peptides as anticancer agents. The primary focus of the current review is to provide insight into the latest research and development in this field and to provide a realistic glimpse into the future of peptide-based therapies for microbe- and virus-induced neoplasms.

Elevated ribosome biogenesis correlates with the rapid growth and progression of cancer. Targeted blockade of ribosome biogenesis induces nucleolar stress, which preferentially leads to the elimination of malignant cells. In this study, it is reported that the nucleolar protein BRIX1 is a critical regulator for the homeostasis between ribosome biogenesis and p53 activation. BRIX1 facilitated the processing of pre-rRNA by supporting the formation of the PeBoW complex. In addition, BRIX1 prevented p53 activation in response to nucleolar stress by impairing the interactions between MDM2 and the ribosomal proteins, RPL5, and RPL11, thereby triggering the resistance of cancer cells to chemotherapy. Conversely, depletion of BRIX1 induced nucleolar stress, which in turn activated p53 through RPL5 and RPL11, consequently inhibiting the growth of tumors. Moreover, engineered exosomes are developed, which are surface-decorated with iRGD, a tumor-homing peptide, and loaded with siRNAs specific to BRIX1, for the treatment of cancer. iRGD-Exo-siBRIX1 significantly suppressed the growth of colorectal cancer and enhanced the efficacy of 5-FU chemotherapy in vivo. Overall, the study uncovers that BRIX1 functions as an oncoprotein to promote rRNA synthesis and dampen p53 activity, and also implies that targeted inhibition of BRIX1 via engineered exosomes can be a potent approach for cancer therapy.

A key challenge in cancer treatment is the effective delivery of drugs into deep regions of tumor tissues, which are impermeable due to abnormal vascular network, increased interstitial fluid pressure (IFP), abundant extra cellular matrix (ECM), and heterogeneity of tumor cells. Cyclic peptides have been used for the surface engineering of nanoparticles to enhance the tumor-penetrating efficacy of drugs. Compared with other surface ligands, cyclic peptides are more easily produced by automated chemical synthesis, and they are featured by their higher binding affinity with their targets, tumor selectivity, stability against degradation, and low toxicity. In this review, different types of cyclic peptides, their physicochemical properties and their in vivo pharmacokinetics are introduced. Next, the progress of cyclic peptide-functionalized drug delivery nanodevices is updated, and the mechanism underlying the tumor-penetrating properties of cyclic peptide-functionalized drug delivery nanodevices is discussed.

Over 20 years have passed since siRNA was brought to the public's attention. Silencing genes with siRNA has been used for various purposes, from creating pest-resistant plants to treating human diseases. In the last six years, several siRNA therapies have been approved by the FDA, which solely target disease-inducing proteins in the liver. The extrahepatic utility of systemically delivered siRNA has been primarily limited to preclinical studies. While siRNA targeting the liver comprises relatively simple ligand-siRNA conjugates, siRNA treating extrahepatic diseases such as cancer often requires complex carriers. The complexity of these extrahepatic carriers of siRNA reduces the likelihood of their widespread clinical use. In the current report, we initially demonstrated that a linear histidine-lysine (HK) carrier of siRNA, injected intravenously, effectively silenced luciferase expressed by MDA-MB-435 tumors in a mouse model. This non-pegylated linear peptide carrier was easily synthesized compared to the complex cRGD-conjugated pegylated branched peptides our group used previously. Notably, the tumor-targeting component, KHHK, was embedded within the peptide, eliminating the need to conjugate the ligand to the carrier. Moreover, brief bath sonication significantly improved the in vitro and in vivo silencing of these HK siRNA polyplexes. Several other linear peptides containing the -KHHK- sequence were then screened with some carriers of siRNA, silencing 80% of the tumor luciferase marker. Additionally, silencing by these HK siRNA polyplexes was confirmed in a second tumor model. Not only was luciferase activity reduced, but these siRNA polyplexes also reduced the Raf-1 oncogene in the MDA-MB-231 xenografts. These simple-to-synthesize, effective, linear HK peptides are promising siRNA carriers for clinical use.

Extracellular vesicles (EVs) are cell-derived vesicles with a phospholipid bilayer measuring 50-150 nm in diameter with demonstrated therapeutic potentials. Limitations such as the natural biodistribution (mainly concentrated in the liver and spleen) and short plasma half-life of EVs present significant challenges to their clinical translation. In recent years, growing research indicated that engineered EVs with enhanced targeting to lesion sites have markedly promoted therapeutic efficacy. However, there is a dearth of systematic knowledge on the recent advances in engineering EVs for targeted delivery. Herein, we provide an overview of the targeting mechanisms, engineering techniques, and clinical translations of natural and engineered EVs in therapeutic applications. Enrichment of EVs at lesion sites may be achieved through the recognition of tissue markers, pathological changes, and the circumvention of mononuclear phagocyte system (MPS). Alternatively, external stimuli, including magnetic fields and ultrasound, may also be employed. EV engineering techniques that fulfill targeting functions includes genetic engineering, membrane fusion, chemical modification and physical modification. A comparative statistical analysis was conducted to elucidate the discrepancies between the diverse techniques on size, morphology, stability, targeting and therapeutic efficacy in vitro and in vivo. Additionally, a summary of the registered clinical trials utilizing EVs from 2010 to 2023 has been provided, with a full discussion on the perspectives. This review provides a comprehensive overview of the mechanisms and techniques associated with targeted delivery of EVs in therapeutic applications to advocate further explorations of engineered EVs and accelerate their clinical applications.

Chemotherapy remains the primary therapeutic approach in treating cancer. The tumor microenvironment (TME) is the complex network surrounding tumor cells, comprising various cell types, such as immune cells, fibroblasts, and endothelial cells, as well as ECM components, blood vessels, and signaling molecules. The often stiff and dense network of the TME interacts dynamically with tumor cells, influencing cancer growth, immune response, metastasis, and resistance to therapy. The effectiveness of the treatment of solid tumors is frequently reduced due to the poor penetration of the drug, which leads to attaining concentrations below the therapeutic levels at the site. Cell-penetrating peptides (CPPs) present a promising approach that improves the internalization of therapeutic agents. CPPs, which are short amino acid sequences, exhibit a high ability to pass cell membranes, enabling them to deliver drugs efficiently with minimal toxicity. Specifically, the iRGD peptide, a member of CPPs, is notable for its capacity to deeply penetrate tumor tissues by binding simultaneously integrins ανβ3/ανβ5 and neuropilin receptors. Indeed, ανβ3/ανβ5 integrins are characteristically expressed by tumor cells, which allows the iRGD peptide to home onto tumor cells. Notably, the respective dual-receptor targeting mechanism considerably increases the permeability of blood vessels in tumors, enabling an efficient delivery of co-administered drugs or nanoparticles into the tumor mass. Therefore, the iRGD peptide facilitates deeper drug penetration and improves the efficacy of co-administered therapies. Distinctively, we will focus on the iRGD mechanism of action, drug delivery systems and their application, and deliberate future perspectives in developing iRGD-conjugated therapeutics. In summary, this review discusses the potential of iRGD in overcoming barriers to drug delivery in cancer to maximize treatment efficiency while minimizing side effects.

This article recounts my journey as a scientist in the early days of extracellular matrix research through the discovery of fibronectin, the RGD sequence as a key recognition motif in fibronectin and other adhesion proteins, and isolation and cloning of integrins. I also discuss more recent work on identification of molecular "zip codes" by in vivo screening of peptide libraries expressed on phage, which led us right back to RGD and integrins. Many disease-specific zip codes have turned out to be based on altered expression of extracellular matrix molecules and integrins. Homing peptides and antibodies recognizing zip code molecules are being used in drug delivery applications, some of which have advanced into clinical trials.

Intercellular communication can be mediated by direct cell-to-cell contact and indirect interactions through secretion of soluble chemokines, cytokines, and growth factors. Extracellular vesicles (EVs) have emerged as important mediators of cell-to-cell and cell-to-environment communications. EVs from tumor cells, immune cells, and stromal cells can remodel the tumor microenvironment and promote cancer cell survival, proliferation, metastasis, immune evasion, and therapeutic resistance. Most importantly, EVs as natural nanoparticles can be manipulated to serve as a potent delivery system for targeted cancer therapy. EVs can be engineered or modified to improve their ability to target tumors and deliver therapeutic substances, such as chemotherapeutic drugs, nucleic acids, and proteins, for the treatment of cancer. This review provides an overview of the biogenesis and recycling of EVs, discusses their roles in cancer development, and highlights their potential as a delivery system for targeted cancer therapy.

The combination therapy of targeted treatments and immune checkpoint blockade (ICB) holds great promise for hepatocellular carcinoma (HCC) treatment. However, challenges such as immunogenicity, off-target toxicity of ICB antibodies, low drug co-delivery efficiency, and lack of effective biomarkers to monitor treatment response limit the efficacy of existing targeted immunotherapies. Herein, we synthesized iRGD-modified pH-sensitive liposomal nanoparticles co-encapsulating lenvatinib (Len) and the small molecule PD-1/PD-L1 inhibitor BMS-202 (iRGD-lip@Len/BMS-202) to address issues related to inadequate tumor enrichment and distinct pharmacokinetics of these drugs. Furthermore, intravoxel incoherent motion-magnetic resonance imaging (IVIM-MRI), which is calculated using a biexponential model, can simultaneously reflect both the diffusion of water molecules within the tissue and the microcirculatory perfusion of capillaries. Consequently, we further assessed the feasibility of using IVIM-MRI to monitor the cancer treatment response in nanodrug therapy. These results demonstrated that the iRGD-targeted liposomal nanodrug effectively accumulated in tumors and released in acidic microenvironments. The sustained release of Len facilitated tumor vascular normalization, decreased the presence of Tregs and MDSCs and activated the IFN-γ signaling pathway. This led to increased PD-L1 expression in tumor cells, enhancing the sensitivity of BMS-202. Consequently, there was a synergistic amplification of antitumor immune therapy, resulting in the shrinkage of subcutaneous and orthotopic HCC and inhibition of lung metastasis. Furthermore, IVIM-MRI technology facilitated the non-invasive monitoring of the tumor microenvironment (TME), revealing critical therapeutic response indicators such as the normalization of tumor blood vessels and the degree of hypoxia. Collectively, the combination of Food and Drug Administration (FDA)-approved drugs with iRGD-modified liposomes presents a promising strategy for HCC treatment. Simultaneously, IVIM-MRI provides a non-invasive method to accurately predict the response to this nanodrug.

To achieve precision and selectivity, anticancer compounds and nanoparticles (NPs) can be targeted with affinity ligands that engage with malignancy-associated molecules in the blood vessels. While tumor-penetrating C-end Rule (CendR) peptides hold promise for precision tumor delivery, C-terminally exposed CendR peptides can accumulate undesirably in non-malignant tissues expressing neuropilin-1 (NRP-1), such as the lungs. One example of such promiscuous peptides is PL3 (sequence: AGRGRLVR), a peptide that engages with NRP-1 through its C-terminal CendR element, RLVR.Here, we report the development of PL3 derivatives that bind to NRP-1 only after proteolytic processing by urokinase-type plasminogen activator (uPA), while maintaining binding to the other receptor of the peptide, the C-domain of tenascin-C (TNC-C). Through a rational design approach and screening of a uPA-treated peptide-phage library (PL3 peptide followed by four random amino acids) on the recombinant NRP-1, derivatives of the PL3 peptide capable of binding to NRP-1 only post-uPA processing were successfully identified. In vitro cleavage, binding, and internalization assays, along with in vivo biodistribution studies in orthotopic glioblastoma-bearing mice, confirmed the efficacy of two novel peptides, PL3uCendR (AGRGRLVR↓SAGGSVA) and SKLG (AGRGRLVR↓SKLG), which exhibit uPA-dependent binding to NRP-1, reducing off-target binding to healthy NRP-1-expressing tissues. Our study not only unveils novel uPA-dependent TNC-C targeting CendR peptides but also introduces a broader paradigm and establishes a technology for screening proteolytically activated tumor-penetrating peptides.

Retinoblastoma is the most common pediatric intraocular malignant tumor affecting 1:15 000-1:20 000 live births. Even though the survival rate in developed countries is over 90 %, more efficient treatment options are needed for better vision salvage and reduction of the adverse effects. Therefore, we investigated fluorescein-labeled PL3 peptide targeting properties towards the Y79 retinoblastoma cell line in vitro. Through the application of cellular imaging and flow cytometry techniques, the PL3 peptide exhibited a rapid and specific internalization within Y79 cells, with subsequent translocation to the cell nuclei, showcasing notable accumulation in the nucleoli. This phenomenon was not present in other investigated cell lines and was not observable with similarly charged and length control peptide. However, the exact mechanism behind this Y79 cell line-specific nuclear and nucleolar targeting pattern remains elusive. In the future, this targeting process could facilitate specific treatment modalities of retinoblastoma with PL3 peptide-coupled drug delivery technologies.

Ultrasmall nanoparticles (usNPs) have emerged as promising theranostic tools in cancer nanomedicine. With sizes comparable to globular proteins, usNPs exhibit unique physicochemical properties and physiological behavior distinct from larger particles, including lack of protein corona formation, efficient renal clearance, and reduced recognition and sequestration by the reticuloendothelial system. In cancer treatment, usNPs demonstrate favorable tumor penetration and intratumoral diffusion. Active targeting strategies, incorporating ligands for specific tumor receptor binding, serve to further enhance usNP tumor selectivity and therapeutic performance. Numerous preclinical studies have already demonstrated the potential of actively targeted usNPs, revealing increased tumor accumulation and retention compared to non-targeted counterparts. In this review, we explore actively targeted inorganic usNPs, highlighting their biological properties and behavior, along with applications in both preclinical and clinical settings.

Immunotherapy has been extensively utilized and studied as a prominent therapeutic strategy for tumors. However, the presence of a hypoxic immunosuppressive tumor microenvironment significantly reduces the efficacy of the treatment, thus impeding its application. In addition, the hypoxic microenvironment can also lead to the enrichment of immunosuppressive cells and reduce the effectiveness of tumor immunotherapy; nanoparticles with biocatalytic activity have the ability to relieve hypoxia in tumor tissues and deliver drugs to target cells and have been widely concerned and applied in the field of tumor therapy. The present study involved the development of a dual nanodelivery system that effectively targets the immune system to modify the tumor microenvironment (TME). The nanodelivery system was developed by incorporating R848 and Imatinib (IMT) into Pt nanozyme loaded hollow polydopamine (P@HP) nanocarriers. Subsequently, their surface was modified with specifically targeted peptides that bind to M2-like macrophages and regulatory T (Treg) cells, thereby facilitating the precise targeting of these cells. When introduced into the tumor model, the nanocarriers were able to selectively target immune cells in tumor tissue, causing M2-type macrophages to change into the M1 phenotype and reducing Treg activation within the tumor microenvironment. In addition, the carriers demonstrated exceptional biocatalytic activity, effectively converting H2O2 into oxygen and water at the tumor site while the drug was active, thereby alleviating the hypoxic inhibitory conditions present in the tumor microenvironment. Additionally, this further enhanced the infiltration of M1-type macrophages and cytotoxic T lymphocytes. Moreover, when used in conjunction with immune checkpoint therapy, the proposed approach demonstrated enhanced antitumor immunotherapeutic effects. The bimodal targeted immunotherapeutic strategy developed in the present study overcomes the drawbacks of traditional immunotherapy approaches while offering novel avenues for the treatment of cancer.

Cancer remains a worldwide problem, and new treatment strategies are being actively developed. Peptides have the characteristics of good biocompatibility, strong targeting, functional diversity, modifiability, membrane permeable ability, and low immunogenicity, and they have been widely used to construct targeted drug delivery systems (DDSs). In addition, peptides, as endogenous substances, have a high affinity, which can not only regulate immune cells but also work synergistically with drugs to kill tumor cells, demonstrating significant potential for application. In this review, the latest progress of polypeptides-based nanocarriers in tumor therapy has been outlined, focusing on their applications in killing tumor cells and regulating immune cells. Additionally, peptides as carriers were found to primarily provide a transport function, which was also a subject of interest to us. At the end of the paper, the shortcomings in the construction of peptide nano-delivery system have been summarized, and possible solutions are proposed therein. The application of peptides provides a promising outlook for cancer treatment, and we hope this article can provide in-depth insights into possible future avenues of exploration.

Peptides are ideal biologicals for targeted drug delivery and have also been increasingly employed as theranostic tools in treating various diseases, including cancer, with minimal or no side effects. Owing to their receptor-specificity, peptide-mediated drug delivery aids in targeted drug delivery with better pharmacological biodistribution. Nanostructured self-assembled peptides and peptide-drug conjugates demonstrate enhanced stability and performance and captivating biological effects in comparison with conventional peptides. Moreover, they serve as valuable tools for establishing interfaces between drug carriers and biological systems, enabling the traversal of multiple biological barriers encountered by peptide-drug conjugates on their journeys to their intended targets. Peptide-based drugs play a pivotal role in the field of medicine and hold great promise for addressing a wide range of complex diseases such as cancer and autoimmune disorders. Nanotechnology has revolutionized the fields of medicine, biomedical engineering, biotechnology, and engineering sciences over the past two decades. With the help of nanotechnology, better delivery of peptides to the target site could be achieved by exploiting the small size, increased surface area, and passive targeting ability of the nanocarrier. Furthermore, nanocarriers also ensure safe delivery of the peptide moieties to the target site, protecting them from degradation. Nanobased peptide delivery systems would be of significant importance in the near future for the successful targeted and efficient delivery of peptides. This review focuses on peptide-drug conjugates and nanoparticle-mediated self-assembled peptide delivery systems in cancer therapeutics.

Breast cancer presents significant challenges due to the limited effectiveness of available treatments and the high likelihood of recurrence. iRGD possesses both RGD sequence and C-terminal sequence and has dual functions of targeting and membrane penetration. iRGD-modified nanocarriers can enhance drug targeting of tumor vascular endothelial cells and penetration of new microvessels, increasing drug concentration in tumor tissues.

The amidation reaction was carried out between SiO2/AuNCs and iRGD/PTX, yielding a conjugated drug delivery system (SiO2/AuNCs-iRGD/PTX, SAIP@NPs). The assessment encompassed the characterization of the morphology, particle size distribution, physicochemical properties, in vitro release profile, cytotoxicity, and cellular uptake of SAIP@NPs. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed using a small animal in vivo imaging system and a tumor-bearing nude mice model, respectively. The tumor targeting and anti-tumor efficacy of SAIP@NPs were assessed utilizing a small animal in vivo imaging system and an in situ nude mice breast cancer xenograft model, respectively.

The prepared SAIP@NPs exhibited decent stability and a certain slow-release effect in phosphate buffer (PBS, pH 7.4). In vitro studies had shown that, due to the dual functions of transmembrane and targeting of iRGD peptide, SAIP@NPs exhibited strong binding to integrin αvβ3, which was highly expressed on the membrane of MDA-MB-231 cells, improving the uptake capacity of tumor cells, inhibiting the rapid growth of tumor cells, and promoting tumor cell apoptosis. The results of animal experiments further proved that SAIP@NPs had longer residence time in tumor sites, stronger anti-tumor effect, and no obvious toxicity to major organs of experimental animals.

The engineered SAIP@NPs exhibited superior functionalities including efficient membrane permeability, precise tumor targeting, and imaging, thereby significantly augmenting the therapeutic efficacy against breast cancer with a favorable safety profile.

RNA therapeutics (RNATx) aim to treat diseases, including cancer, by targeting or employing RNA molecules for therapeutic purposes. Amongst the most promising targets are long non-coding RNAs (lncRNAs), which regulate oncogenic molecular networks in a cell type-restricted manner. lncRNAs are distinct from protein-coding genes in important ways that increase their therapeutic potential yet also present hurdles to conventional clinical development. Advances in genome editing, oligonucleotide chemistry, multi-omics and RNA engineering are paving the way for efficient and cost-effective lncRNA-focused drug discovery pipelines. In this Review, we present the emerging field of lncRNA therapeutics for oncology, with emphasis on the unique strengths and challenges of lncRNAs within the broader RNATx framework. We outline the necessary steps for lncRNA therapeutics to deliver effective, durable, tolerable and personalized treatments for cancer.

Cancer treatment with vascular disrupting agents (VDAs) causes rapid and extensive necrosis in solid tumors. However, these agents fall short in eliminating all malignant cells, ultimately leading to tumor regrowth. Here, we investigated whether the molecular changes in the tumor microenvironment induced by VDA treatment sensitize the tumors for secondary nanotherapy enhanced by clinical-stage tumor penetrating peptide iRGD. Treatment of peritoneal carcinomatosis (PC) and breast cancer mice with VDA combretastatin A-4 phosphate (CA4P) resulted in upregulation of the iRGD receptors αv-integrins and NRP-1, particularly in the peripheral tumor tissue. In PC mice treated with CA4P, coadministration of iRGD resulted in an approximately threefold increase in tumor accumulation and a more homogenous distribution of intraperitoneally administered nanoparticles. Notably, treatment with a combination of CA4P, iRGD, and polymersomes loaded with a novel anthracycline Utorubicin (UTO-PS) resulted in a significant decrease in the overall tumor burden in PC-bearing mice, while avoiding overt toxicities. Our results indicate that VDA-treated tumors can be targeted therapeutically using iRGD-potentiated nanotherapy and warrant further studies on the sequential targeting of VDA-induced molecular signatures.