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Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by poor water solubility, easy inactivation, and severe toxicity. Structural modifications and nanoformulations represent two crucial avenues for camptothecin's development. However, the potential for further structural modifications is limited, and camptothecin nanoparticles fabricated via physical loading have the drawbacks of low drug loading and leakage. Prodrug‐based CPT nanoformulations have shown unique advantages, including increased drug loading, reduced burst release, improved bioavailability, and minimal toxic side effects. Stimulus‐responsive CPT nano‐prodrugs that respond to various endogenous or exogenous stimuli by introducing various activatable linkers to achieve spatiotemporally responsive drug release at the tumor site. This review comprehensively summarizes the latest research advances in stimulus‐responsive CPT nano‐prodrugs, including preparation strategies, responsive release mechanisms, and their applications in cancer therapy. Special focus is placed on the release mechanisms and characteristics of various stimulus‐responsive CPT nano‐prodrugs and their application in cancer treatment. Furthermore, clinical applications of CPT prodrugs are discussed. Finally, challenges and future research directions for CPT nano‐prodrugs are discussed. This review to be valuable to readers engaged in prodrug research is expected. [ABSTRACT FROM AUTHOR]

Inflammation‐associated diseases are very common clinically with a high incidence; however, there is still a lack of effective treatments. Cell‐biomimetic nanoplatforms have led to many breakthroughs in the field of biomedicine, significantly improving the efficiency of drug delivery and its therapeutic implications especially for inflammation‐associated diseases. Macrophages are an important component of immune cells and play a critical role in the occurrence and progression of inflammation‐associated diseases while simultaneously maintaining homeostasis and modulating immune responses. Therefore, macrophage‐biomimetic nanoplatforms not only inherit the functions of macrophages including the inflammation tropism effect for targeted delivery of drugs and the neutralization effect of pro‐inflammatory cytokines and toxins via membrane surface receptors or proteins, but also maintain the functions of the inner nanoparticles. Macrophage‐biomimetic nanoplatforms are shown to have remarkable therapeutic efficacy and excellent application potential in inflammation‐associated diseases. In this review, inflammation‐associated diseases, the physiological functions of macrophages, and the classification and construction of macrophage‐biomimetic nanoplatforms are first introduced. Next, the latest applications of different macrophage‐biomimetic nanoplatforms for the treatment of inflammation‐associated diseases are summarized. Finally, challenges and opportunities for future biomedical applications are discussed. It is hoped that the review will provide new ideas for the further development of macrophage‐biomimetic nanoplatforms. [ABSTRACT FROM AUTHOR]

Antibacterial photocatalytic therapy (APCT) is one of the most promising non‐antibiotic treatment strategies for biofilm‐infected wounds and inflammation caused by drug‐resistant bacteria. However, it still faces issues such as inadequate single antibacterial capacity and lack of antioxidant capacity. In this study, a Z‐scheme heterojunction (Bi2S3‐X@PDA) is designed using a polydopamine (PDA) shell firmly anchored to the surface of sulfur vacancy‐rich bismuth sulfide nanorods (Bi2S3‐X NRs). Under near‐infrared light and hydrogen peroxide, Bi2S3‐X@PDA significantly improves the photocatalytic efficiency of reactive oxygen species generation and shows a nearly 100% broad‐spectrum antibacterial effect against multiple bacterial strains and bacterial biofilms in vitro. Interestingly, the antioxidant activity of the PDA shell in Bi2S3‐X@PDA remarkably downregulates the expression of pro‐inflammatory factors and promotes macrophage reprogramming toward the proregenerative M2 phenotype. In a mouse wound model of methicillin‐resistant Staphylococcus aureus biofilm infection, Bi2S3‐X@PDA effectively eliminates drug‐resistant bacterial biofilms through APCT/mild photothermal therapy, while reducing inflammation in normal tissues and regulating the immune microenvironment, thereby promoting rapid wound healing. Overall, this light‐controlled treatment strategy, which provides both antibacterial and anti‐inflammatory functions, is a reliable tool for combating biofilm infection and inflammation caused by drug‐resistant bacteria. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a critical global health challenge, with current treatments limited by the complex MI microenvironment, particularly the excessive oxidative stress and intense inflammatory responses that exacerbate cardiac dysfunction and MI progression. Herein, a mannan‐based nanomedicine, Que@MOF/Man, is developed to target the inflammatory infarcted heart and deliver the antioxidative and anti‐inflammatory agent quercetin (Que), thereby facilitating a beneficial myocardial microenvironment for cardiac repair. The presence of mannan on the nanoparticle surface enables selective internalization by macrophages rather than cardiomyocytes. Que@MOF/Man effectively neutralizes reactive oxygen species in macrophages to reduce oxidative stress and promote their differentiation into a reparative phenotype, reconciling the inflammatory response and enhancing cardiomyocyte survival through intercellular communication. Owing to the recruitment of macrophages into inflamed myocardium post‐MI, in vivo, administration of Que@MOF/Man in MI rats revealed the specific distribution into the injured myocardium compared to free Que. Furthermore, Que@MOF/Man exhibited favorable results in resolving inflammation and protecting cardiomyocytes, thereby preventing further myocardial remodeling and improving cardiac function in MI rats. These findings collectively validate the rational design of an inflammation‐targeted delivery strategy to mitigate oxidative stress and modulate the inflammation response in the injured heart, presenting a therapeutic avenue for MI treatment. [ABSTRACT FROM AUTHOR]

Methicillin‐resistant Staphylococcus aureus (MRSA) biofilm infection, caused by impaired glucose metabolism in diabetic foot patients, poses a significant obstacle to the healing process and carries a high risk of being life‐threatening. Due to microvascular occlusion and the entrenchment of MRSA biofilms in diabetic foot, controlling and effectively treating MRSA infection remains challenging. Traditional hydrogels suffer from swelling‐related mechanical issues and inadequate drug release control, limiting their applications as biomimetic extracellular matrices for wound healing. Herein, a double‐network hydrogel composed of polyvinyl alcohol, sodium alginate, and gelatin (PSG) loaded with tea polyphenol self‐assembled magnesium nanoparticles (TP‐Mg NPs) with antibacterial and angiogenic properties for treating MRSA‐infected diabetic foot wounds under hyperglycemic conditions is constructed. TP‐Mg@PSG exhibits enhanced mechanical strength and toughness for wound attachment and recovery movement torsion. In the acidic infection microenvironment representative of MRSA‐infected wounds, the TP‐Mg@PSG hydrogel degrades to release TP‐Mg NPs, showing excellent anti‐MRSA biofilm effect and high biocompatibility. Such localized controlled release enhances the inhibition of MRSA infection and reduces the inflammatory response in rats, promoting cell proliferation and rapid wound repair. Therefore, this study presents a multifunctional biomaterial system for managing diabetic foot conditions, highlighting its potential for clinical applications. [ABSTRACT FROM AUTHOR]

Despite the tremendous progress in cancer treatment in recent decades, cancers often become resistant due to multiple mechanisms, such as intrinsic or acquired multidrug resistance, which leads to unsatisfactory treatment effects or accompanying metastasis and recurrence, ultimately to treatment failure. With a deeper understanding of the molecular mechanisms of tumors, researchers have realized that treatment designs targeting tumor resistance mechanisms would be a promising strategy to break the therapeutic deadlock. Nanodelivery systems have excellent physicochemical properties, including highly efficient tissue‐specific delivery, substantial specific surface area, and controllable surface chemistry, which endow nanodelivery systems with capabilities such as precise targeting, deep penetration, responsive drug release, multidrug codelivery, and multimodal synergy, which are currently widely used in biomedical researches and bring a new dawn for overcoming cancer resistance. Based on the mechanisms of tumor therapeutic resistance, this review summarizes the research progress of nanodelivery systems for overcoming tumor resistance to improve therapeutic efficacy in recent years and offers prospects and challenges of the application of nanodelivery systems for overcoming cancer resistance. [ABSTRACT FROM AUTHOR]

Bone defects in osteoporosis usually present excessive reactive oxygen species (ROS), abnormal inflammation levels, irregular shapes and impaired bone regeneration ability; therefore, osteoporotic bone defects are difficult to repair. In this study, an injectable thermosensitive hydrogel poly (D, L‐lactide)‐poly (ethylene glycol)‐ poly (D, L‐lactide) (PLEL) system containing resveratrol (Res) and dexamethasone (DEX) is designed to create a microenvironment conducive to osteogenesis in osteoporotic bone defects. This PLEL hydrogel is injected and filled irregular defect areas and achieving a rapid sol‐gel transition in situ. Res has a strong anti‐inflammatory effects that can effectively remove excess free radicals at the damaged site, guide macrophage polarization to the M2 phenotype, and regulate immune responses. Additionally, DEX can promote osteogenic differentiation. In vitro experiments showed that the hydrogel effectively promoted osteogenic differentiation of mesenchymal stem cells, removed excess intracellular ROS, and regulated macrophage polarization to reduce inflammatory responses. In vivo experiments showed that the hydrogel promoted osteoporotic bone defect regeneration and modulated immune responses. Overall, this study confirmed that the hydrogel can treat osteoporotic bone defects by synergistically modulating bone damage microenvironment, alleviating inflammatory responses, and promoting osteogenesis; thus, it represents a promising drug delivery strategy to repair osteoporotic bone defects. [ABSTRACT FROM AUTHOR]

Selenium (Se) and vitamin B2 (VitB2) all play essential roles in participating in hepatic lipid metabolism regulation. In this study, we aimed to identify whether Se combined with VitB2 could meliorate nonalcoholic fatty liver disease (NAFLD) caused by high‐fat (HF) diet in rats. To this end, 50 SD male rats were randomly allotted into five groups equally after receiving a HF diet for 2 weeks. Rats were fed high‐fat diets and gavaged daily with 0.83 or 8.33 µg kg–1 Se combined with 0.70 or 3.50 mg kg–1 VitB2 for 8 weeks. Another 10 rats were given a conventional diet as a control group. The result showed that Se combined with VitB2 decreased NAFLD activity score and liver lipid's levels, relieved hepatic steatosis and lipid deposition and promoted the balance of ApoA1/ApoB ratio. The hepatic 3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase (HMGR) level was declined, and the serum HL level was increased in NAFLD rats through the combined intervention. In addition, Se and VitB2 regulated hepatic metabolism factor's (FAS, ACC, ACAT1, PPARγ, and SREBP‐1c) expression level. Taken together, the combined intervention of Se and VitB2 can alleviate HF‐diet‐induced NAFLD in rats. The molecular mechanism may be related to affecting the activities of lipid metabolic enzymes such as FAS, ACC, HMGR, ACAT1, and HL by inhibiting the expression of PPARγ and SREBP‐1c. Practical Applications: The present study showed that a combination of Se and VitB2 can effectively reduce hepatic lipid accumulations, exert hepatoprotective effects and regulate hepatic lipid metabolism in NAFLD rats caused by a high‐fat diet. The possible molecular mechanism may be related to affecting the activities of lipid metabolic enzymes such as FAS, ACC, HMGR, ACAT1, and HL, and inhibiting the expression of PPARγ and SREBP‐1c. Se and VitB2 cosupplementation may be a potential therapeutic strategy in overcoming hepatic lipid disorders' adverse effects beyond pharmacological interventions to ameliorate NAFLD. [ABSTRACT FROM AUTHOR]

Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first‐line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti‐tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications. [ABSTRACT FROM AUTHOR]

The endometrium is a unique human tissue with an extraordinary ability to undergo a hormone‐regulated cycle encompassing shedding, bleeding, scarless repair, and regeneration throughout the female reproductive cycle. The cyclical repair and regeneration of the endometrium manifest as changes in endometrial epithelialization, glandular regeneration, and vascularization. The mechanisms encompass inflammation, coagulation, and fibrinolytic system balance. However, specific conditions such as endometriosis or TCRA treatment can disrupt the process of cyclical endometrial repair and regeneration. There is uncertainty about traditional clinical treatments' efficacy and side effects, and finding new therapeutic interventions is essential. Researchers have made substantial progress in the perspective of regenerative medicine toward maintaining cyclical endometrial repair and regeneration in recent years. Such progress encompasses the integration of biomaterials, tissue‐engineered scaffolds, stem cell therapies, and 3D printing. This review analyzes the mechanisms, diseases, and interventions associated with cyclical endometrial repair and regeneration. The review discusses the advantages and disadvantages of the regenerative interventions currently employed in clinical practice. Additionally, it highlights the significant advantages of regenerative medicine in this domain. Finally, we review stem cells and biologics among the available interventions in regenerative medicine, providing insights into future therapeutic strategies. [ABSTRACT FROM AUTHOR]

The hypoxic tumor microenvironment (TME) significantly affects cancer treatment. Conventional chemotherapeutic agents cannot effectively target hypoxic tumor tissue, which decreases efficacy and results in severe toxic side effects. To alleviate this problem, a self‐driving biomotor is developed by functionalizing MCDP nanoparticles containing calcium peroxide and doxorubicin (DOX) loaded onto polydopamine‐coated metal–organic frameworks（MOF）, with the anaerobic Bifidobacterium infantis (Bif) for synergistic chemotherapy and chemodynamic therapy (CDT) against breast cancer. The materials of institute Lavoisier (MIL) frameworks + CaO2 + DOX + polydopamine (MCDP)@Bif biohybrid actively targets hypoxic regions of solid tumors via the inherent targeting ability of Bif. Once it has accumulated in the tumor tissue, MCDP generates hydroxyl radicals through the enhanced Fenton‐type reactions between Fe2+ and self‐generated hydrogen peroxide in the acidic TME. The disruption of Ca2+ homeostasis and resulting mitochondrial Ca2+ overload triggers apoptosis and enhances oxidative stress, promoting tumor cell death. The results found that the DOX concentration in MCDP@Bif‐treated tumors is 3.8 times higher than that in free‐DOX‐treated tumors, which significantly prolongs the median survival of the tumor‐bearing mice to 69 days and reduces the toxic side effects of DOX. Therefore, the novel bacteria‐driven drug delivery system is highly effective in achieving synergistic chemotherapy and CDT against solid tumors. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a promising therapy for refractory cancer based on the cytotoxic reaction of 10B (n, α) 7Li. Although two BNCT agents are clinically available, they are quickly metabolized and show modest enrichment in tumor sites, partially limiting BNCT widespread application. Consequently, novel agents that perform active targeting and show good biocompatibility have to be developed. Herein, boronophenylalanine‐containing polydopamine (B‐PDA) nanoparticles are easily fabricated by encapsulating boronophenylalanine (BPA) in polydopamine via nitrogen‐boronate coordination. In this study, B‐PDA achieves increased tumor accumulation and prolonged retention effects in the tumor site and superior antitumor activity post neutron irradiation in the orthotopic xenograft glioma model. In brief, this study offers a novel strategy for BPA delivery and may broaden the perspective on nanomedicine design for BNCT. [ABSTRACT FROM AUTHOR]

Synergistic photothermal immunotherapy has emerged as a favorable therapeutic approach to fight cancer. However, design of an effective photothermal immunotherapy system to suppress tumor growth and simultaneously inhibit tumor metastases continues to be a challenge. Here a dual toll‐like receptor agonists delivery system CPG@Au NRs/m‐R848 for combined photothermal immunotherapy of melanoma is developed. CPG@Au NRs/m‐R848 displays strong antitumor effects by promoting maturation of dendritic cells (DCs) and reprogramming of M2 macrophages into M1 phenotype. Moreover, immunogenic cell death (ICD) induced by photothermal ablation of Au NRs could synergistically produce in situ vaccination effect with CPG ODN and R848, generating systemic and lasting antitumor immunity. It is further proved that CPG@Au NRs/m‐R848 treatment inhibits tumor growth in bilateral B16F10 tumors model by eliciting CD8+ T cell response. Overall, this work suggests that this strategy hold great potential in tumor immunotherapy by regulating tumor‐associated macrophage polarization, triggering DCs maturation and inducing ICD. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second‐ranking malignancy in hematological tumors. The pathogenesis of MM is complex with high heterogeneity, and the development of the disease is a multistep process. Chromosomal translocations, aneuploidy, genetic mutations, and epigenetic aberrations are essential in disease initiation and progression. The correlation between MM cells and the bone marrow microenvironment is associated with the survival, progression, migration, and drug resistance of MM cells. In recent decades, there has been a significant change in the paradigm for the management of MM. With the development of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, chimeric antigen receptor T‐cell therapies, and novel agents, the survival of MM patients has been significantly improved. In addition, nanotechnology acts as both a nanocarrier and a treatment tool for MM. The properties and responsive conditions of nanomedicine can be tailored to reach different goals. Nanomedicine with a precise targeting property has offered great potential for drug delivery and assisted in tumor immunotherapy. In this review, we summarize the pathogenesis and current treatment options of MM, then overview recent advances in nanomedicine‐based systems, aiming to provide more insights into the treatment of MM. [ABSTRACT FROM AUTHOR]

Peptide‐drug conjugates (PDCs) are an important class of therapeutic agents that combine one or more active molecules with a short peptide via a biodegradable spacer to generate prodrugs. Here an antioxidant (i.e., 3,5‐dihydroxybenzoic acid), a non‐steroidal anti‐inflammatory drug (i.e., ibuprofen, IPF), and a self‐assembled peptide motif (i.e., Gly‐Phe‐Phe‐Tyr‐Asp, GFFYD) are integrated to produce a peptide‐drug amphiphile, which self‐assembles to form hydrogel and further exerts the synergistic effects, and consequently emerges high therapeutic efficacy. In the in vitro study toward lipopolysaccharide‐activated RAW264.7 macrophages, the resulting hydrogel significantly reduces the production of cytokines (e.g., IL‐1β, IL‐6 and tumor necrosis factor‐α (i.e., TNF‐α)) compared with that of native IPF via the inhibition of nuclear factor‐κB (i.e., NF‐κB), janus kinase‐signal transducer and activator of transcription (i.e., JAK‐STAT) signals and NLR family pyrin domain containing 3 (i.e., NLRP3) inflammasome activation. Moreover, a rabbit model of endotoxin induced uveitis evidences the superior therapeutic efficacy of the resulting hydrogel over that of clinically used 0.1 wt% diclofenac sodium eyedrop. Overall, this work offers new insights into the anti‐inflammatory mechanism of PDCs hydrogel and presents the therapeutic values in the treatment of ocular disorders, and ultimately fulfils the potential clinical benefits of PDCs. [ABSTRACT FROM AUTHOR]

Background: Left bundle branch pacing (LBBP) is a new near‐physiological pacing modality. Distinguishing left ventricular septal only pacing (LVSP) from nonselective LBBP still needs clarification. This prospective study sought to establish a differentiation algorithm to confirm LBBP. Methods and Results: LBBP was attempted in consecutive patients. If direct LBB capture (LBBP) could not be confirmed, LVSP was considered to have been achieved. Intracardiac left ventricular (LV) activation sequence and activation time were analyzed using coronary sinus (CS) electrogram mapping. Electrophysiological parameters including S‐CSmax, S‐CSmin, LV lateral wall activation time, ΔLV, and LBB potential were compared between LBBP and LVSP. Stimulated LV activation time (S‐LVAT) and stimulated QRS duration (S‐QRSd) were also compared between the two groups. Multivariate logistic regression analysis was used to develop a prediction algorithm for LBBP. Of the 43 prospectively enrolled patients, 27 underwent LBBP and 16 underwent LVSP. All LBBP patients showed identical LV activation sequences to their intrinsic rhythm while no LVSP patients maintained their intrinsic sequence. S‐CSmax, ΔLV, LV lateral wall activation time, and S‐LVAT during LBBP were significantly shorter than those during LVSP. Combining LBB potential with S‐LVAT had the largest area under the curve (AUC) of 0.985 for confirming LBBP with a sensitivity of 95.2% and a specificity of 93.7%. Conclusions: Compared with LVSP, LBBP preserves a normal LV activation sequence and better electrical synchrony. A combination of LBB potential with S‐LVAT can be an effective and practical model to distinguish LBBP from LVSP during implantation in patients with normal LBB activation. [ABSTRACT FROM AUTHOR]

Focal therapy, or partial gland ablation, represents the middle ground between active surveillance and definitive treatment strategies against localized prostate cancer (PCa), among which the ultrasound‐ and light‐mediated focal therapies are quite promising. Herein, for the first time in the literature, a novel polysaccharide‐based nanoprodrug is fabricated for synergistic sonodynamic therapy and phototherapy against localized PCa. Specifically, the cyanine dye IR806 is conjugated to chondroitin sulfate (CS) via disulfide linkages to obtain CS‐ss‐IR806 (CSR) conjugates, which then self‐assemble to form CSR nanoparticles (NPs) with properties of enhanced endocytosis, redox/hyaluronidase‐responsiveness, and mitochondria‐targeted ability. In contrast to free sensitizers, CSR NPs reveal dramatically enhanced water solubility, substantially lower dark toxicity, and superior biocompatibility. Encouragingly, favorable hyperthermia and high reactive oxygen species generation are observed on exposing CSR NPs to combined sono/photoirradiation. In a PCa tumor‐bearing mice model, intratumoral injection with a markedly low dose of CSR NPs followed by dual‐irradiation results in superior trimodal anticancer efficacy when compared with either monoirradiation strategy. Such synergistic antitumor efficacy is further demonstrated to be associated with the common and complementary mechanisms of sonotherapy and phototherapy. This work provides a promising approach as a next‐generation focal therapy strategy against localized PCa. [ABSTRACT FROM AUTHOR]

Increasing evidence has suggested that chemotherapeutics affect the integrity of the intestinal barrier and alter the intestinal microbiota, thus limiting the therapeutic outcomes of cancer chemotherapy. Docetaxel (DTX) is used for breast cancer treatment and has gastrointestinal side effects, but the influence of DTX formulations on the intestinal barrier and intestinal microbiota remains unknown. Therefore, in this work, the influence of DTX injection (free DTX, commercial formulation) and DTX/methoxy poly(ethylene glycol)‐block‐poly(D,L‐lactide) (mPEG‐PDLLA) (DTX micelles, nanoformulation) on the integrity of the intestinal barrier and the intestinal microbiota is investigated. It is found that the free DTX causes significantly greater intestinal barrier damage than the DTX micelles. The diversity of the intestinal microbiota, and the relative abundance of Akkermansia muciniphila and Ruminococcus gnavus in the DTX micelle‐treated group is significantly higher than that in the free DTX‐treated group. Moreover, the tumor growth rate is elevated in antibiotic mixture‐pretreated mice, demonstrating that the diversity and composition of the intestinal microbiota may be associated with tumor progression. This work demonstrates that different formulations of chemotherapeutics have different effects on the integrity of the intestinal barrier and the intestinal microbiota. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in humans. The inhibition of peptidyl‐prolyl cis/trans isomerase (Pin1) gene expression may have great potential in the treatment of HCC. N‐Acetylgalactosamine (GalNAc) was used to target the liver. Cholesterol‐modified antimicrobial peptide DP7 (DP7‐C) acts as a carrier, the GalNAc‐siRNA/DP7‐C complex increases the uptake of GalNAc‐siRNA and the escape of endosomes in hepatocytes. In addition, DP7‐C nanoparticles and hydrogel‐assisted GalNAc‐Pin1 siRNA delivery can effectively enhance the stability and prolong the silencing effects of Pin1 siRNA. In an orthotopic liver cancer model, the GalNAc‐Pin1 siRNA/DP7‐C/hydrogel complex can potentially regulate Pin1 expression in hepatocellular carcinoma cells and effectively inhibit tumor progression. Our study proves that Pin1 siRNA is an efficient method for the treatment of HCC and provides a sustainable and effective drug delivery system for the suppression of liver cancer. [ABSTRACT FROM AUTHOR]

The interaction of nanoparticles (NPs) with proteins and the formation of protein corona in the biological fluids are of great interest and significance for drug delivery. In the past decade, the corona formation in the blood and its impacts on the in vitro and in vivo fate of NPs has been well investigated and reviewed. Recently, more and more attention is paid to the nano–protein interactions taking place in the gastrointestinal tract (GIT) between the orally administered NPs and the digestive enzymes. The enzyme corona formed in the GIT can significantly affect the properties, gastrointestinal transit, and oral absorption of NPs. Since oral delivery is the most preferred delivery route, comprehensively understanding the corona formation in the GIT and its impacts on oral delivery NPs are of great importance. Herein, we aim to summarize the recent updates on the nano–protein interactions between NPs and digestive enzymes, and launch an interesting discussion on the potentials of using the digestive enzyme corona for the colon targeted delivery. [ABSTRACT FROM AUTHOR]

The diagnosis of malignant tumors is essential for informing clinical decisions regarding therapeutic options. Current imaging and pathological diagnostic methods do not provide quantitative molecular information that is important in tumor identification. Moreover, pathological tissue analysis is dependent on unevenly distributed pathological features. The tumor microenvironment has been documented to have hydrogen peroxide (H2O2). This study presents a biologically sensitive and efficient H2O2 electrochemical sensor based on PtNi nanoparticle‐doped N‐reduced graphene oxide (PtNi‐N‐rGO) with a low detection limit (2.8 × 10–9m), a fast response time (<6 s) and desirable anti‐interference characteristics. Herein, H2O2 is used as molecular biomarker. The sensor successfully captures H2O2 from cancer cells. In addition, it efficiently detects tumor tissues, adjacent tissues, and normal tissues. This study demonstrates the H2O2 sensor potential to rapidly detect tumor tissues. This technique provides a complementary method for pathological tumor diagnosis that is independent of the traditional pathology labs. [ABSTRACT FROM AUTHOR]

Acquired chemoresistance presents a major clinical impediment, which is an urgent problem to be solved. Interestingly, myeloma cell leukemia‐1 (MCL‐1) and folate receptor expression levels are higher in chemotherapy‐resistant patients than in pretreatment patients. In this study, a multifunctional folic acid (FA)‐targeting core–shell structure is presented for simultaneous delivery of shMCL‐1 and paclitaxel (PTX). The transfection efficiency of shMCL‐1 with the FA‐targeting delivery system is higher than with a nontargeting delivery system in Skov3 and A2780T cells. The FA‐targeting system significantly inhibits cell growth, blocks cell cycles, and promotes apoptosis of cancer cells in vitro. The mechanisms involved in inhibiting growth are related to Bcl‐2/Bax and cdc2/Cyclin B1 pathways. An analysis of RNA sequencing suggests that shMCL‐1 reverses chemoresistance through regulating genes such as regulator of chromosome condensation 2 (RCC2). The synergetic effect of shMCL‐1 and PTX effectively inhibits tumor growth in both PTX‐resistant and normal cancer models by inducing tumor apoptosis, inhibiting proliferation, and limiting tumor angiogenesis. The study results indicate that a FA‐targeting delivery system combining shMCL‐1 with PTX can simultaneously target tumor sites and restore the sensitivity of chemotherapy‐resistant cancer to PTX. These findings have important implications for patients with normal or PTX‐resistant cancer. [ABSTRACT FROM AUTHOR]

Background: Chronic right ventricular (RV) pacing is associated with an increased incidence of heart failure and mortality. Left bundle branch (LBB) pacing could produce near‐physiological electrical activation and mechanical synchrony. We aimed to report the effects of upgrading to LBB pacing in heart failure patients after chronic RV pacing. Methods: The indications included pacing‐induced cardiomyopathy (PICM) in Group 1 and heart failure after RV pacing with left ventricular ejection fraction (LVEF) ≥ 50% in Group 2. LBB pacing was achieved by penetrating the pacing lead to the subendocardium of left‐sided interventricular septum through the venous access. Left ventricular activation time (LVAT) was measured from the pacing stimulus to the ascending peak of lead V5 or V6. All patients underwent clinical and echocardiographic evaluations before and after upgrading. Results: Totally 27 patients (13 in Group 1 and 14 in Group 2) were consecutively enrolled. The mean follow‐up time after upgrade was 10.4 ± 6.1 months. Paced QRS duration was significantly shortened from 174.1 ± 15.8 milliseconds to 116.6 ± 11.7 milliseconds (p <.0001). The mean LVAT was 83.2 ± 11.7 milliseconds. LVEF increased from 40.3 ± 5.2% before upgrading to 48.1 ± 9.5% at follow‐up in patients with PICM. Serum N‐terminal probrain natriuretic peptide levels decreased and New York Heart Association classification improved in both groups. No upgrade‐related complications were observed. Conclusions: Upgrading to LBB pacing was feasible and effective with improved cardiac function in heart failure patients with both reduced and preserved LVEF after RV pacing. [ABSTRACT FROM AUTHOR]

Minimizing drug leakage in systemic circulation, synchronizing the in vivo fate of multiple drugs, and precisely controlling tumor locoregional drug release, remain challenging for nanomedicine‐based cancer therapy. Here, a reactive oxygen species (ROS)‐responsive camptothecin (CPT) prodrug delivery system (MPEG‐(TK‐CPT)‐PPa) is developed, in which CPT and photosensitizer pyropheophorbide‐a (PPa) are concurrently conjugated to the same poly(ethylene glycol) methyl ether (MPEG) via ROS‐responsive thioketal (TK) and lipid linkage. The synthesized MPEG‐(TK‐CPT)‐PPa conjugate self‐assembles to form nanoparticles (NPs) (43.6 ± 0.8 nm) in solution. The covalently conjugated prodrug prevents drug leakage during systemic circulation and synchronizes the in vivo distribution of the two drugs. The generated fluorescence signal of PPa helps precisely track and locate the NPs at tumor sites. Under the guidance of imaging, a near‐infrared laser locally irradiates tumor tissue upon reaching the strongest fluorescence. The ROS generated by PPa not only cleaves the TK linkage and then triggers locoregional, controllable and on‐demand CPT release, but also exhibits cytotoxic effects on tumor cells. Thus, CPT‐mediated chemotherapy and PPa‐induced photodynamic therapy lead to the combined and enhanced suppression of tumor growth. Accordingly, such laser‐triggered, localized, controllable, and on‐demand drug release systems may provide an alternative option for CPT formulations. [ABSTRACT FROM AUTHOR]

Erlotinib (ERT), oral administration agents, is one of the most pivotal targeted drugs in the treatment of non‐small cell lung cancer (NSCLC); however, its poor solubility, low oral bioavailability, and capricious toxicity limit broader clinical applications. In this paper, a novel injectable matrix is prepared based on hollow mesoporous silica nanoparticles (HMSNs) and thermosensitive poly(d,l‐lactide)‐poly(ethylene glycol)‐poly(d,l‐lactide) (PDLLA‐PEG‐PDLLA, PLEL) hydrogel to encapsulate and localize the sustained release of ERT for improved efficacy against NSCLC. The test‐tube‐inversion method shows that this ERT‐loaded hydrogel composite (ERT@HMSNs/gel) presents as an injectable flowing solution under room temperature and transfers into a physically crosslinked non‐flowing gel structure at physiological temperature.The ERT@HMSNs/gel composite shows a much longer intratumoral and peritumoral drug retention by in vivo imaging study. Notably, this injectable drug delivery system (DDS) provides an impressive balance between antitumor efficacy and systemic safety in a mice xenograft model. The novel ERT loaded HMSNs/gel system may be a promising candidate for the in situ treatment of NSCLC. Moreover, this study provides a prospective platform for the design and fabrication of a nano‐scaled delivery system for localized anticancer therapies. [ABSTRACT FROM AUTHOR]

The combination of chemotherapy and photodynamic therapy (PDT) has promising potential in the synergistic treatment of cancer. However, chemotherapy and photodynamic synergistic therapy are impeded by uncontrolled chemotherapeutics release behavior, targeting deficiencies, and hypoxia‐associated poor PDT efficacy in solid tumors. Here, a platinum nanozyme (PtNP) loaded reactive oxygen species (ROS)‐responsive prodrug nanoparticle (CPT‐TK‐HPPH/Pt NP) is created to overcome these limitations. The ROS‐responsive prodrug consists of a thioketal bond linked with camptothecin (CPT) and photosensitizer‐2‐(1‐hexyloxyethyl)‐2‐devinyl pyropheophorbide‐a (HPPH). The PtNP in CPT‐TK‐HPPH/Pt NP can efficiently catalyze the decomposition of hydrogen peroxide (H2O2) into oxygen to relieve hypoxia. The production of oxygen can satisfy the consumption of HPPH under 660 nm laser irradiation to attain the on‐demand release of CPT and ensure enhanced photodynamic therapy. As a tumor diagnosis agent, the results of photoacoustic imaging and fluorescence imaging for CPT‐TK‐HPPH/Pt NP exhibit desirable long circulation and enhanced in vivo targeting. CPT‐TK‐HPPH/Pt NPs effectively inhibit tumor proliferation and growth in vitro and in vivo. CPT‐TK‐HPPH/Pt NP, with its excellent ROS‐responsive drug release behavior and enhanced PDT efficiency can serve as a new cancer theranostic agent, and will further promote the research of chemophotodynamic synergistic cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Left bundle branch area pacing (LBBAP) was reported to improve cardiac function by correcting complete left bundle branch block (CLBBB). Our study aimed to compare the efficacy of LBBAP and biventricular pacing (BIVP) in heart failure patients with CLBBB. Methods: Ten patients prospectively underwent LBBAP (LBB‐CRT group) and 30 patients received BIVP (BIV‐CRT group) were matched using propensity score matching. LBBAP was achieved by the trans‐interventricular septum method. Echocardiography, electrocardiogram, NYHA classification, and blood B‐type natriuretic peptide concentration were evaluated at preimplantation and at 6‐month follow up. CRT response was defined as at least 15% decrease in left ventricular end‐systolic volume. Results: In the LBB‐CRT group, CLBBB were successfully corrected by LBBAP with no complications. QRS duration (QRSd) significantly decreased after implantation in both groups, and the decrease of QRSd in the LBB‐CRT group was significantly greater than that in the BIV‐CRT group (60.80 ± 20.09 vs. 33.00 ± 21.48 ms, p =.0009). The echocardiographic measurements including left ventricular end‐diastolic diameter, left ventricular end‐systolic diameter, and left ventricular ejection fraction significantly improved after 6 months in both groups. The response rate was significantly higher in LBB‐CRT group than BIV‐CRT group (100.00% vs. 63.33%, p =.038). The percentage of patients in New York Heart Association classification Grades I and II was significantly higher in the LBB‐CRT group compared with that in the BIV‐CRT group (median 1.5 vs. 2.0, p =.029) at 6‐month follow‐up. Conclusions: It is effective and safe to correct CLBBB with LBBAP in heart failure patients. Compared with BIVP, LBBAP can better optimize electrical synchrony and improve cardiac function. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronization therapy (CRT) is the standard‐of‐care therapy for the patients with heart failure and left ventricular (LV) dyssynchrony. However, approximately 30% of the patients show no response. Recent studies have shown that His bundle pacing (HBP) could be an alternative for the patients with CRT indications. The purpose of this study was to evaluate the efficacy of HBP in patients with heart failure. Methods: We searched PubMed and Embase databases for studies evaluating HBP in patients with heart failure and LV dyssynchrony. The successful rate of implantation, QRS duration, pacing threshold, LV function at baseline and follow‐up, and mortality rates were extracted and summarized. Results: Eleven studies including 494 patients were included in this analysis. The overall successful rate for implantation was 82.4%. The main indications for HBP were CRT candidates and cardiomyopathy with atrial fibrillation undergoing atrioventricular node ablation. Permanent HBP resulted in narrow QRS duration of 116.3 ± 13.9 ms after implantation. LV functions, including echocardiographic parameters and clinical outcomes, significantly improved at follow‐up (P < 0.001). However, there was a trend of increased capture and bundle branch block correction thresholds at follow‐up compared to baseline (P = 0.01 and 0.02, respectively). During a mean follow‐up of 23.7 months, 5.9% of the patients experienced heart failure‐related hospitalization and the mortality rate was 9.1%. Conclusion: Permanent HBP has shown promising results for heart failure patients in small observational studies. Randomized controlled trials are needed to assess the efficacy of HBP in these patients. [ABSTRACT FROM AUTHOR]

The wide clinical application of photodynamic therapy (PDT) is hampered by poor water solubility, low tumor selectivity, and nonspecific activation of photosensitizers, as well as tumor hypoxia which is common for most solid tumors. To overcome these limitations, tumor‐targeting, redox‐activatable, and oxygen self‐enriched theranostic nanoparticles are developed by synthesizing chlorin e6 (Ce6) conjugated hyaluronic acid (HA) with reducible disulfide bonds (HSC) and encapsulating perfluorohexane (PFH) within the nanoparticles (PFH@HSC). The fluorescence and phototoxicity of PFH@HSC nanoparticles are greatly inhibited by a self‐quenching effect in an aqueous environment. However, after accumulating in tumors through passive and active tumor‐targeting, PFH@HSC appear to be activated from “OFF” to “ON” in photoactivity by the redox‐responsive destruction of the vehicle's structure. In addition, PFH@HSC can load oxygen within lungs during blood circulation, and the oxygen dissolved in PFH is slowly released and diffuses over the entire tumor, finally resulting in remarkable tumor hypoxia relief and enhancement of PDT efficacy by generating more singlet oxygen. Taking advantage of the excellent imaging performance of Ce6, the tumor accumulation of PFH@HSC can be monitored by fluorescent and photoacoustic imaging after intravenous administration into tumor‐bearing mice. This PFH@HSC nanoparticle might have good potential for dual imaging‐guided PDT in hypoxic solid tumor treatment.The designed oxygen self‐enriched and redox‐activatable PFH@HSC nanoparticles exhibit unique characteristics as follows: (i) excellent tumor selectivity: passive and active tumor‐targeting mediated by an EPR effect and receptor‐mediated endocytosis; (ii) oxygen self‐sufficiency: delivering sufficient oxygen to tumors to enhance PDT efficacy; (iii) redox‐based activatable theranostics: redox‐activatable fluorescence/photoacoustic dual‐imaging‐guided highly efficient PDT with low side effects. [ABSTRACT FROM AUTHOR]

Abstract: The therapeutic outcome of photothermal therapy (PTT) remains impeded by the transparent depth of light. Combining PTT with immunotherapy provides strategies to solve this problem. Regulating metabolism‐related enzymes is a promising strategy to stimulate immune response. Here, a nanosystem (NLG919/IR780 micelles) with the properties of photothermal conversion and regulation of the tryptophan metabolic pathway is used to suppress the growth of the tumor margin beyond effective PTT and promote tumor PTT and immunotherapy. It is revealed that mild heat treatment promotes the growth of the tumor margin beyond effective PTT for the upregulation of heat shock protein (HSP), indoleamine 2,3‐dioxygenase (IDO), and programmed death‐ligand 1 (PD‐L1). The NLG919/IR780 micelles can effectively inhibit the activity of IDO but do not affect the level of IDO expression. NLG919/IR780 micelles can effectively accumulate in the tumor and can migrate to lymph nodes and the lymphatic system. In vivo antitumor studies reveal that NLG919/IR780 micelles effectively suppress the growth of tumor margin following PTT in primary tumors. NLG919/IR780 micelle‐mediated PTT and IDO inhibition further stimulate the activation of T lymphocytes, inhibiting the growth of distal tumors (abscopal effect). The results demonstrate that the NLG919/IR780 micelles combine PTT and immunotherapy and suppress the tumor margin as well as distal tumor growth post photothermal therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: The incidence and clinical outcomes of delayed response to cardiac resynchronization therapy (CRT) have not been well clarified. We aimed to observe the incidence and prognosis of delayed response and to identify its possible mechanisms. Methods: A total of 115 CRT patients were retrospectively analyzed in our study. Patients who met the enrollment criteria were divided into two groups: group A, conventional responders who showed response at 1‐year follow‐up, and group B, delayed responders who showed response after 1‐year follow‐up. CRT response was defined as an absolute increase of ≥10% in left ventricular ejection fraction. Results: Fifty‐two patients (61 ± 12 years, 37 male) experienced conventional response to CRT and 17 patients (63 ± 11 years, 10 male) experienced delayed response. The mean follow‐up time was 5.2 ± 2.4 years. The incidence of delayed response was 14.8% (17/115). All‐cause mortality and hospitalization rates for heart failure were similar for delayed and conventional responders. Multivariate logistic regression analysis revealed that scar burden > 35% was an independent predictor of CRT delayed response (odds ratio 8.794, P  =  0.038). Conclusions: A significant proportion of patients demonstrated delayed response to CRT. The delayed responders had a good prognosis that was similar to that of conventional responders. More scar burden might be related to the incidence of delayed response. [ABSTRACT FROM AUTHOR]

Background Implantable cardioverter defibrillators (ICDs) have become the standard approach for prevention of sudden cardiac death. Whether ICD therapy is an independent predictor of all-cause mortality is controversial. We made the systematic review and meta-analysis to estimate the impact of ICD therapy on mortality. Methods We searched the PubMed and Embase databases for studies evaluating the effect of ICD shocks or antitachycardia pacing (ATP) on mortality. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random effects models. Results Thirteen cohort studies were identified. Mean ejection fraction of the population was 23-35%; 68.0% had ischemic etiology, and 74.5% received a primary prevention ICD implantation. Appropriate shocks were an independent predictor of increased mortality compared with no-shock or no-therapy patients (HR 2.07, 2.76, respectively). In contrast, inconsistent results were obtained during inappropriate-shock analyses: when compared with no-shock patients, inappropriate shocks were associated with an increased risk of death (HR 1.54, 95% CI: 1.25-1.89, P < 0.0001); however, when compared to no-therapy patients, there was no relationship between inappropriate shocks and mortality (HR 1.20, 95% CI: 0.90-1.61, P = 0.22). Subgroup analysis in heart failure patients also did not find any difference in mortality between inappropriate-shock and no-therapy patients. No increased risk of mortality was found in the patients who experienced appropriate or inappropriate ATP only. Conclusion Appropriate shocks were associated with an increased mortality in ICD patients. However, whether inappropriate shocks worsened the clinical outcome was controversial, and larger prospective trials are needed to clarify the issue. [ABSTRACT FROM AUTHOR]

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin-polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin-15 (IL15) and investigated the effects HPEI-plasmid IL15 (HPEI-pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI-pIL15 complexes on lung metastases of B16-F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI-pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K-pIL15 and PEI25K-pIL15, and mice treated with HPEI-pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor-α and interferon-γ in the serum also increased in the pIL15-treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI-pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI-pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol. ( Cancer Sci 2011; 102: 1403-1409) [ABSTRACT FROM AUTHOR]

In this work, a biodegradable poly(ethylene glycol)‐poly(ε‐caprolactone)‐poly (ethylene glycol) (PEG‐PCL‐PEG, PECE) triblock copolymer was successfully synthesized, which was flowing sol at low temperature and turned to nonflowing gel at body temperature. The toxicity evaluation of PECE hydrogel as a potential in situ sustained opthalmic drug delivery system was performed, including the biodegradability of PECE hydrogel in the eye, its effect on cultured human lens epithelia, intraocular pressure, and ocular tissues. The results indicated that the prepared PECE hydrogel was biocompatible and biodegradable despite of temporary elevated intraocular pressure and slight corneal endothelial damage at specific concentration. Therefore, PECE hydrogel may be a safe candidate for sustained ophthalmic drug delivery system. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 2010 [ABSTRACT FROM AUTHOR]

Cancer diagnosis, H 2O 2 detection, H 2O 2 electrochemical sensors, PtNi-N-rGO nanocomposites, tissue monitoring Keywords: cancer diagnosis; H 2O 2 detection; H 2O 2 electrochemical sensors; PtNi-N-rGO nanocomposites; tissue monitoring EN cancer diagnosis H 2O 2 detection H 2O 2 electrochemical sensors PtNi-N-rGO nanocomposites tissue monitoring 1 1 1 05/17/21 20210501 NES 210501 In article number 2001212, Yan Yu, Jinrong Peng, Zhiyong Qian, and co-workers developed a biologically sensitive and efficient H SB 2 sb O SB 2 sb electrochemical sensor based on PtNi-N-rGO nanocomposites. [Extracted from the article]

Cancer therapy is unsatisfactory as it typically has serious side effects, because normal cells in healthy organs are destroyed along with the tumor. Thus, researchers have tried to develop effective therapies with minimal side effects. One such method is to use nanotechnology to carry the drugs or therapeutic agents to the tumor region by secure encapsulation without leakage. Once the nanomedicine enters the target tumor site, it can release therapeutic agents in an effective manner. Accordingly, various nanomedicines have been developed to enhance the efficiency of cancer therapy and minimize the systematic toxicity. Here, we provide an overview and discuss the different types of responsive nanomedicines including physically, chemically, biologically, dual, and multi‐responsive nanomedicines, for the in situ release of cargos in recent years. We propose critical considerations that must be considered for the design of excellent stimuli‐nanomedicine. Furthermore, the possible directions for the development of successful stimuli‐responsive (smart) nanomedicine are highlighted. With the development of responsive nanomedicines, precise and personalized nanomedicine will be realized with great promise in the future. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology [ABSTRACT FROM AUTHOR]

Melanoma, the most aggressive skin cancer type, is challenging to treat due to its high metastatic potential and low response to conventional therapies. Innovative approaches, including combination therapies, are crucial for enhancing treatment efficacy while minimizing side effects. It is developed boronophenylalanine‐containing polydopaine (B‐PDA) nanoparticles by encapsulating boronophenylalanine in polydopamine through nitrogen‐boronate coordination, targeting both boron neutron capture therapy (BNCT) and photothermal therapy (PTT). With stability and biocompatibility under physiological conditions, these nanoparticles utilize the phenylalanine residues in BPA to target the overexpressed neutral amino acid transporter 1 (LAT1) in melanoma cells, resulting in enhanced cell‐specific targeting. B‐PDA nanoparticles demonstrated significant photothermal effects under external stimulation, inducing localized heating and triggering heterogeneous tumor cell death, thereby enhancing sensitivity to BNCT. Combining BNCT and PTT, the B‐PDA nanoparticles offer a promising strategy for melanoma treatment. [ABSTRACT FROM AUTHOR]

Nanomedicine constructed by therapeutics has unique and irreplaceable advantages in biomedical applications, especially in drug delivery for cancer therapy. The strategy, however, used to construct the therapeutics‐based nanomedicines with tumor microenvironmental factor responsiveness is still sophisticated. In this study, an easy‐operating procedure is used to construct a therapeutics‐based nanosystem with active tumor‐targeting, enhanced penetration, and stimuli‐responsive drug release behavior as well as programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) blockading mediated immunomodulation to enhance tumor immunotherapy. The matrix metalloproteinase‐2 responsive peptide with the existence of Lyp‐1 sequence contributes to the success of active tumor‐targeting and the enhancement of the penetration of the nanoparticles in tumor tissue. The obtained nanosystem strikingly inhibits the primary tumor growth in the first 24 h (more than 97.5% of tumor cells are inhibited), and total inhibition can be achieved with the combination of photothermal therapy. IR820, which is served as the carrier for the therapeutics, is used as a photosensitizer for photothermal therapy. The progress and aggression of distal tumor has further been alleviated by a d‐peptide which is an antagonist for PD‐1/PD‐L1 blockage. Therefore, a therapeutics‐constructed multifunctional nanosystem is provided to realize a combinational therapeutic strategy to enhance the therapeutic outcome. [ABSTRACT FROM AUTHOR]