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Effective tumor treatment depends on optimizing drug penetration and accumulation in tumor tissue while minimizing systemic toxicity. Nanomedicine has emerged as a key solution that addresses the rapid clearance of free drugs, but achieving deep drug penetration into solid tumors remains elusive. This review discusses various strategies to enhance drug penetration, including manipulation of the tumor microenvironment, exploitation of both external and internal stimuli, pioneering nanocarrier surface engineering, and development of innovative tactics for active tumor penetration. One outstanding strategy is organelle-affinitive transfer, which exploits the unique properties of specific tumor cell organelles and heralds a potentially transformative approach to active transcellular transfer for deep tumor penetration. Rigorous models are essential to evaluate the efficacy of these strategies. The patient-derived xenograft (PDX) model is gaining traction as a bridge between laboratory discovery and clinical application. However, the journey from bench to bedside for nanomedicines is fraught with challenges. Future efforts should prioritize deepening our understanding of nanoparticle-tumor interactions, re-evaluating the EPR effect, and exploring novel nanoparticle transport mechanisms. [Display omitted] •Models for assessing drug penetration into tumors are compared.•Strategies for structural transformation of nanomedicine in the tumor environment are comprehensively elaborated.•Strategies to overcome tumor barriers for deep penetration are provided.•Active tumor penetration is introduced.•The potential and hurdles of nanomedicine in tumor therapies are concluded.

A stimuli‐responsive polymeric prodrug‐based nanotheranostic system with imaging agents (cyanine5.5 and gadolinium‐chelates) and a therapeutic agent paclitaxel (PTX) is prepared via polymerization and conjugating chemistry. The branched polymeric PTX‐Gd‐based nanoparticles (BP‐PTX‐Gd NPs) demonstrate excellent biocompatibility, and high stability under physiological conditions, but they stimuli‐responsively degrade and release PTX rapidly in a tumor microenvironment. The in vitro behavior of NPs labeled with fluorescent dyes is effectively monitored, and the NPs display high cytotoxicity to 4T1 cells similar to free PTX by impairing the function of microtubules, downregulating anti‐apoptotic protein Bcl‐2, and upregulating the expression of Bax, cleaved caspase‐3, cleaved caspase‐9, cleaved‐PARP, and p53 proteins. Great improvement in magnetic resonance imaging (MRI) is demonstrated by these NPs, and MRI accurately maps the temporal change profile of the tumor volume after injection of NPs and the tumor treatment process is also closely correlated with the T1 values measured from MRI, demonstrating the capability of providing real‐time feedback to the chemotherapeutic treatment effectiveness. The imaging‐guided chemotherapy to the 4T1 tumor in the mice model achieves an excellent anti‐tumor effect. This stimuli‐responsive polymeric nano‐agent opens a new door for efficient breast cancer treatment under the guidance of fluorescence/MRI. This study demonstrates a strategy to fabricate stimuli‐responsive branched polymeric prodrug‐based theranostic nanomedicine. The anticancer mechanism is studied well and the in vitro and vivo behaviors including biodistribution, retention, and anticancer efficacy can be monitored well by imaging. This stimuli‐responsive polymeric demonstrates great potential of a platform for cancer nanotheranostics.

Nanozyme catalytic therapy for cancer treatments has become one of the heated topics, and the therapeutic efficacy is highly correlated with their catalytic efficiency. In this work, three copper‐doped CeO2 supports with various structures as well as crystal facets are developed to realize dual enzyme‐mimic catalytic activities, that is superoxide dismutase (SOD) to reduce superoxide radicals to H2O2 and peroxidase (POD) to transform H2O2 to ∙OH. The wire‐shaped CeO2/Cu‐W has the richest surface oxygen vacancies, and a low level of oxygen vacancy (Vo) formation energy, which allows for the elimination of intracellular reactive oxygen spieces (ROS) and continuous transformation to ∙OH with cascade reaction. Moreover, the wire‐shaped CeO2/Cu‐W displays the highest toxic ∙OH production capacity in an acidic intracellular environment, inducing breast cancer cell death and pro‐apoptotic autophagy. Therefore, wire‐shaped CeO2/Cu nanoparticles as an artificial enzyme system can have great potential in the intervention of intracellular ROS in cancer cells, achieving efficacious nanocatalytic therapy. A high degree of surface oxygen mobility and a low level of oxygen vacancy formation energy is exposed over the CeO2/Cu‐W surface, which is employed as a mimetic enzyme of superoxide dismutase (SOD) to convert O2∙‐ →H2O2 and peroxidase (POD) to realize H2O2→∙OH for oncotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with no efficacious treatment. The application of nanomedicine is expected to bring new hope to PDAC treatment. In this study, we report a novel supramolecular dendrimeric nanosystem carrying the anticancer drug doxorubicin, which demonstrated potent anticancer activity, markedly overcoming the heterogeneity of drug response and resistance of primary cultured tumor cells derived from PDAC patients. This dendrimer nanodrug was constructed with a fluorinated amphiphilic dendrimer, which self‐assembled into micelles nanostructure and encapsulated doxorubicin with high loading. Because of the fine nanosize, stable formulation and acid‐promoted drug release, this dendrimeric nanosystem effectively accumulated in tumor, with deep penetration in tumor tissue and rapid drug uptake/release profile in cells, ultimately resulting in potent anticancer activity and complete suppression of tumor growth in patient‐derived xenografts. Most importantly, this dendrimer nanodrug generated uniform and effective response when treating 35 primary pancreatic cancer cell lines issued from patient samples as a robust platform for preclinical drug efficacy testing. In addition, this dendrimer nanodrug formulation was devoid of adverse effects and showed excellent tolerability. Given all these uniquely advantageous features, this simple and convenient dendrimer nanodrug holds great promise as a potential candidate to treat the deadly PDAC. A novel supramolecular dendrimeric nanosystem carrying the anticancer drug doxorubicin was developed in this study. We demonstrated this nanosystem markedly overcoming the heterogeneity of drug response and resistance of primary cultured tumor cells derived from 35 PDAC patients. This simple and convenient dendrimer nanodrug holds great promise as a potential candidate to treat the deadly PDAC.

Combined chemotherapy and targeted therapy holds immense potential in the management of advanced gastric cancer (GC). GC tissues exhibit an elevated expression level of protein kinase B (AKT), which contributes to disease progression and poor chemotherapeutic responsiveness. Inhibition of AKT expression through an AKT inhibitor, capivasertib (CAP), to enhance cytotoxicity of paclitaxel (PTX) toward GC cells is demonstrated in this study. A cathepsin B‐responsive polymeric nanoparticle prodrug system is employed for co‐delivery of PTX and CAP, resulting in a polymeric nano‐drug BPGP@CAP. The release of PTX and CAP is triggered in an environment with overexpressed cathepsin B upon lysosomal uptake of BPGP@CAP. A synergistic therapeutic effect of PTX and CAP on killing GC cells is confirmed by in vitro and in vivo experiments. Mechanistic investigations suggested that CAP may inhibit AKT expression, leading to suppression of the phosphoinositide 3‐kinase (PI3K)/AKT signaling pathway. Encouragingly, CAP can synergize with PTX to exert potent antitumor effects against GC after they are co‐delivered via a polymeric drug delivery system, and this delivery system helped reduce their toxic side effects, which provides an effective therapeutic strategy for treating GC. A cathepsin B‐responsive polymeric nanoparticle prodrug system is established for co‐delivery of paclitaxel (PTX) and capivasertib (CAP) to obtain BPGP@CAP, which selectively accumulates in the tumor tissue and releases PTX and CAP in response to overexpressed cathepsin B in lysosomes to exert a synergistic therapeutic effect to eradicate gastric cancer cells.

At present, the 10-year survival rate of patients with pancreatic cancer is still less than 4%, mainly due to the high cancer recurrence rate caused by incomplete surgery and lack of effective postoperative adjuvant treatment. Systemic chemotherapy remains the only choice for patients after surgery; however, it is accompanied by off-target effects and server systemic toxicity. Herein, we proposed a biodegradable microdevice for local sustained drug delivery and postoperative pancreatic cancer treatment as an alternative and safe option. Biodegradable poly(l-lactic-co-glycolic acid) (P(L)LGA) was developed as the matrix material, gemcitabine hydrochloride (GEM·HCl) was chosen as the therapeutic drug and polyethylene glycol (PEG) was employed as the drug release-controlled regulator. Through adjusting the amount and molecular weight of PEG, the controllable degradation of matrix and the sustained release of GEM·HCl were obtained, thus overcoming the unstable drug release properties of traditional microdevices. The drug release mechanism of microdevice and the regulating action of PEG were studied in detail. More importantly, in the treatment of the postoperative recurrence model of subcutaneous pancreatic tumor in mice, the microdevice showed effective inhibition of postoperative in situ recurrences of pancreatic tumors with excellent biosafety and minimum systemic toxicity. The microdevice developed in this study provides an option for postoperative adjuvant pancreatic treatment, and greatly broadens the application prospects of traditional chemotherapy drugs.

Supramolecular self‐assemblies of dendritic peptides with well‐organized nanostructures have great potential as multifunctional biomaterials, yet the complex self‐assembly mechanism hampers their wide exploration. Herein, a self‐stabilized supramolecular assembly (SSA) constructed from a PEGylated dendritic peptide conjugate (PEG‐dendritic peptide‐pyropheophorbide a, PDPP), for augmenting tumor retention and therapy, is reported. The supramolecular self‐assembly process of PDPP is concentration‐dependent with multiple morphologies. By tailoring the concentration of PDPP, the supramolecular self‐assembly is driven by noncovalent interactions to form a variety of SSAs (unimolecular micelles, oligomeric aggregates, and multi‐aggregates) with different sizes from nanometer to micrometer. SSAs at 100 nm with a spherical shape possess extremely high stability to prolong blood circulation about 4.8‐fold higher than pyropheophorbide a (Ppa), and enhance tumor retention about eight‐fold higher than Ppa on day 5 after injection, which leads to greatly boosting the in vivo photodynamic therapeutic efficiency. RNA‐seq demonstrates that these effects of SSAs are related to the inhibition of MET‐PI3K‐Akt pathway. Overall, the supramolecular self‐assembly mechanism for the synthetic PEGylated dendritic peptide conjugate sheds new light on the development of supramolecular assemblies for tumor therapy. A self‐stabilized supramolecular assembly (SSA) from the PEGylated dendritic peptide conjugate is presented, which builds on the concentration‐dependent supramolecular self‐assembly that demonstrates ultrahigh colloidal stability and enhanced tumor retention to boost its photodynamic therapeutic efficiency. This study reveals the supramolecular self‐assembly mechanism of SSAs and further expands the advanced functions of dendritic peptides in the field of cancer therapy.

Tumor microenvironment‐responsive imaging‐guided therapy has emerged as a novel approach for malignant tumor prognosis and therapy. A multifunctional nanoscale drug delivery system is often employed to realize diagnosis, treatment, monitoring, and evaluation by combining a therapeutic unit and an imaging unit to enable. In this study, we designed and prepared a theranostic nanomedicine by conjugating a small‐molecular gadolinium chelate (Diethylenetriaminepentaacetic acid Gadolinium[III] chelate, Gd‐DOTA) and a chemotherapeutic drug paclitaxel (PTX) via a cathepsin B‐responsive linker (glycylphenylalanylleucylglycine, Gly‐Phe‐Leu‐Gly, GFLG) onto a peptide dendron‐hyaluronic acid (HA) hybrid. Upon reaching the tumor microenvironment, the GFLG linker was cleaved by overexpressed cathepsin B, leading to simultaneous release of PTX for targeted chemotherapy and Gd‐DOTA for enhanced magnetic resonance imaging (MRI). The experiments demonstrated that the theranostic nanomedicine significantly enhanced MRI contrast and exhibited superior antitumor efficacy in 4T1 breast tumor models without pronounced systemic toxicity. Importantly, under the tumor microenvironment, effective release and clearance of Gd‐DOTA from the hybrid postimaging reduced the risk of long‐term toxicity. This study presents a feasible approach for cancer theranostics by integrating precise imaging, targeted therapy, and rapid clearance of toxic drugs in a single platform. This promising nanomedicine could be explored for clinical translation. The Dendronized‐HA‐GFLG‐Gd/PTX based theranostic agent could self‐assemble into a nanoparticle structure. After the GFLG linker was cleaved in a tumor microenvironment containing overexpressed cathepsin B, Gd‐DOTA was released from the nanomedicine once the MR image acquisition was complete and PTX achieved its targeted delivery into tumor cells.

Full-thickness cutaneous wounds pose a significant threat to global health due to their complex healing demands. Standard clinical wound dressings often fall short in providing the adaptability and functionality required for the entire healing process. While hierarchically engineered nanofiber dressings have shown advancement in wound management, challenges such as material compatibility and interfacial bonding during their design have limited both manufacturing and therapeutic outcomes. This study introduces a self-adhesive hierarchical nanofiber (SAHN) patch designed to provide a comprehensive and dynamic approach to wound care. The SAHN patch strategically integrates synthetic biodegradable poly(ester carbonate) with natural bioactive components, forming a seamless dual-layer system that offers both immediate protection and sustained bioactivity to support tissue regeneration. In vitro and in vivo studies demonstrate the patch’s superior interlayer adhesion, soft tissue adhesion, controlled degradation, and robust antibacterial capabilities. These features collectively safeguard the wound microenvironment, facilitate hemostasis, manage inflammation, and accelerate wound closure. Our findings highlight the transformative potential of the SAHN patch in improving traditional wound care, overcoming the manufacturing challenges associated with hierarchical nanofiber dressings, and offering a promising solution for dynamic and multistage management of full-thickness cutaneous wounds that aligns with the natural progression of tissue repair. Graphical Abstract

Background Nanocarriers-derived antitumor therapeutics are often associated with issues of limited tumor penetration and dissatisfactory antitumor efficacies. Some multistage delivery systems have been constructed to address these issues, but they are often accompanied with complicated manufacture processes and undesirable biocompatibility, which hinder their further application in clinical practices. Herein, a novel dual-responsive multi-pocket nanoparticle was conveniently constructed through self-assembly and cross-linking of amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates to enhance tumor penetration and antitumor efficacy. Results The multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. But once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (< 20 nm) nanoparticles, promoting deep penetration and distribution in tumor tissues. Furthermore, MPNs exhibited not only an excellent stable nanostructure for antitumor doxorubicin (DOX) loading, but rapid dissociation of the nanostructure under an intracellular reductive environment. With the capacity of long blood circulation, deep tumor penetration and fast intracellular drug release, the DOX-loaded multi-pocket nanoparticles demonstrated superior antitumor activities against large 4T1 tumor (~ 250 mm 3 ) bearing mice with reduced side effect. Conclusions Our facile fabrication of multi-pocket nanoparticles provided a promising way in improving solid tumor penetration and achieving a great therapeutic efficacy. Graphic Abstract