Feng Jiang

Solid tumors, the most prevalent form of malignancy, pose therapeutic challenges distinct from hematologic malignancies due to their complex biology, including high tumor heterogeneity, a dense extracellular matrix (ECM), an immunosuppressive tumor microenvironment (TME), and multifaceted drug resistance. Peptide drugs have emerged as a focal point in precision oncology, combining the deep tissue penetration of small molecules with the high target specificity, low immunogenicity, and sequence designability of antibodies. This review systematically summarizes advancements in peptide‐based therapeutics for solid tumors from 2020 to 2025. These agents are categorized by function into five classes: tumor‐homing peptides, surface receptor antagonist/inhibitory peptides, interfering peptides, peptide vaccines, and cell‐penetrating peptides as delivery tools. We also highlight the transformative role of artificial intelligence (AI) in peptide design and discovery. Finally, we discuss outcomes from clinical trials of peptide drugs in solid tumors, underscoring their potential as multifunctional agents in this setting.

To overcome multidrug resistance (MDR) in chemotherapy, a redox-responsive self-assembling nanoprodrug was developed for codelivering gemcitabine (Gem) and the P-glycoprotein (P-gp) inhibitor quinine (Qu). Initially, Gem and Qu were conjugated via a disulfide bond to form the Gem-Qu (GQ) prodrug, but its poor self-assembly capability (forming unstable nanoaggregates) limited its further use. To address this problem, GQ was modified using 3,3′-dithiodipropionic acid or adipic acid to improve the aqueous solubility, yielding GQ-S and GQ-C, respectively. It is noteworthy that both GQ-S and GQ-C could self-assemble into spherical nanoparticles (GQ-S NPs and GQ-C NPs) with uniform size and excellent stability. GQ-S NPs exhibited a hydrodynamic diameter of approximately 147.5 nm, while GQ-C NPs were around 180.5 nm, both with low polydispersity indices. Under tumor-mimicking redox conditions (elevated glutathione or H₂O₂), GQ-S NPs released approximately 30% of Gem and 48% of Qu simultaneously, whereas Gem release from GQ-C NPs remained below 10%, confirming the enhanced dual redox-responsiveness of GQ-S NPs. Cellular uptake in U251 and U87 glioma cells was efficient for both nanoparticles. GQ-S NPs demonstrated greater cytotoxicity, with an IC₅₀ of 1.560 ± 0.123 μM in U251 cells─7-fold and 2.7-fold lower than that of free Gem and GQ-C NPs, respectively. Mechanistic studies revealed that GQ-S NPs induced apoptosis and markedly suppressed P-gp expression, and promoted intracellular Gem accumulation. In summary, GQ-S NPs integrate the advantages of carrier-free design, low toxicity, high stability, and redox-responsive release, offering a promising strategy for targeted combination therapy in drug-resistant glioblastoma.

Multi-stimuli-responsive nanoprodrug implementing a “chemo-differentiation–cancer stem cell inhibition” strategy toward triple-negative breast cancer therapy.

Gemcitabine (GTB), a clinically approved nucleoside analogue for cancer treatment, faces therapeutic limitations due to rapid enzymatic deactivation by cytidine deaminase (CDA) in tumor microenvironments. Over 90% of systemically administered GTB undergoes catalytic conversion to inactive 2'-deoxy-2',2'-difluorouracil metabolites through CDA-mediated deamination. To address this pharmacological challenge, we developed a multifunctional codelivery nanosystem through strategic engineering of reactive oxygen species (ROS)-generating, mitochondria-targeting CPUL1-TPP (CT) nanoaggregates. These self-assembling CT/GTB complexes were further optimized with DSPE-MPEG2k (DP) and Angiopep-2-conjugated DSPE-MPEG2k (Ang-DP) to create blood-brain barrier (BBB)-penetrating Ang-DP@CT/GTB nanoparticles, enhancing both physiological stability and low-density lipoprotein receptor-related protein 1 (LRP1)-mediated glioma targeting. Comparative analyses revealed that Ang-DP@CT/GTB nanoparticles significantly enhanced GTB's antiglioblastoma efficacy compared to free drug administration in both in vitro and in vivo models. Mechanistic investigations demonstrated that the nanosystem upregulates heme oxygenase-1 (HO-1), subsequently downregulating CDA expression to mitigate GTB metabolism. This coordinated molecular modulation prolongs GTB's therapeutic activity while leveraging the ROS-generating capacity of CT components for synergistic tumor suppression. The BBB-permeable codelivery platform exemplifies a rational design paradigm for multifunctional carrier-free pure nanodrugs (PNDs), demonstrating how clinical drug reformulation can overcome inherent pharmacokinetic limitations. This nanotechnology-driven approach provides critical insights for optimizing chemotherapeutic performance through metabolic pathway regulation and targeted delivery engineering.

Thirty‐seven novel chalcone‐phenazine hybrid molecules (C1∼C13 and F1∼F24) with 1,2,3‐triazole or ethyl group as linkers were designed and synthesized in this study. Some compounds exhibited selective cytotoxicity against U87‐MG cancer cell lines in vitro, in which compound C4 were found to have the best antiproliferative activity. SAR study indicated 1,2,3‐triazole group may be crucial for enhancing compounds’ cytotoxicity. C4 was verified to induce ferroptosis in U87‐MG cells by transcription, lipid peroxidation, lipid ROS assays. Furthermore, C4 was up‐regulated LC3‐II, degradated FTH1, and then increasing iron resulted in the down‐regulation of NCOA4. Together, all above evidences highlighted the potential of compound C4 that triggered ferroptosis by activating ferritinophagy against U87‐MG cells.