Combination chemotherapy for malignant tumors effectively overcomes monotherapy resistance through multi-pathway synergistic mechanisms. However, its clinical implementation remains constrained by the inherent physicochemical disparity between hydrophilic and hydrophobic drugs. A representative example is the combination of paclitaxel (PTX) and doxorubicin (DOX): PTX inhibits tumor cell division by stabilizing microtubules, while DOX intercalates into DNA to block replication, demonstrating marked synergistic efficacy in breast cancer treatment (Zhao et al., 2017, Jouybari et al., 2019). Nevertheless, conventional sequential administration fails to achieve optimal therapeutic synergy due to pharmacokinetic mismatches (DOX half-life ≈30 h vs. PTX ≈5 h), which cause spatiotemporal imbalances in intratumoral drug concentrations (Gustafson et al., 2005, Berg et al., 1994, Duska et al., 1999). More critically, conventional nanocarriers cannot reconcile the divergent loading requirements of hydrophilic/hydrophobic drugs, frequently resulting in suboptimal encapsulation efficiency and premature burst release—key barriers to clinical translation (Thedrattanawong et al., 2018, Kita and Dittrich, 2011). These challenges underscore the imperative to develop advanced delivery systems that integrate three critical functionalities within a unified platform: differential drug loading, intelligent targeting, and spatiotemporally synchronized release.

Existing co-delivery systems, including liposomes and polymeric micelles, face intrinsic design conflicts (Chen et al., 2023, Gao et al., 2025). Enhancing carrier hydrophobicity to improve PTX loading capacity inevitably compromises DOX encapsulation efficiency (Missirlis et al., 2006). While antibody-mediated targeting improves tumor accumulation, fixed epitope recognition limits adaptability to tumor heterogeneity, and batch-to-batch variability of biologics hinders clinical reproducibility (Zichi et al., 2008, Anderson et al., 2008). Furthermore, conventional carriers often exhibit phase separation during co-loading of hydrophilic/hydrophobic drugs, leading to heterogeneous drug distribution and uncontrolled release profiles (Winkler et al., 2019). Most critically, reliance on passive targeting or static release mechanisms prevents dynamic responsiveness to tumor microenvironmental cues, resulting in insufficient drug concentrations at target sites and systemic off-target toxicity (Manzari et al., 2021, Zang et al., 2022). Collectively, these limitations necessitate the development of intelligent, programmable platforms with integrated functionalities to meet the demands of precision combination chemotherapy.

The rapid advancement of nanotechnology has created unprecedented opportunities in biomedical applications, particularly in cancer treatment and tissue engineering (Tian et al., 2025, Liang et al., 2021, Nasibova et al., 2024, Khalilov et al., 2024, Salahshour et al., 2024). Building upon these developments, recent progress in functional nucleic acids (FNAs) offers transformative solutions to longstanding challenges in these fields (Xie et al., 2023, Jia et al., 2024, Zheng et al., 2025). Unlike antibodies, aptamers achieve dynamic recognition of diverse tumor biomarkers through programmable sequence design and conformation-dependent binding (Safarkhani et al., 2024, Sun et al., 2024), exhibiting nanomolar affinity while eliminating batch variability through chemical synthesis, this property gives aptamers excellent specificity, enabling precise targeting of target sites (Al Borhani et al., 2024). Moreover, DNA duplexes enable molecularly precise DOX loading via base-pair intercalation, effectively circumventing phase separation issues inherent to lipid-based systems (Zhang et al., 2022, Majzner et al., 2024). The stimuli-responsive nature of DNA further allows engineering of microenvironment-triggered release mechanisms. This unique integration of targeting, loading, and response functionalities establishes FNAs as pivotal building blocks for next-generation intelligent nanocarriers.

In this work, we engineered a functional nucleic acid-driven poly (lactic-co-glycolic acid) hybrid nano-system through molecular design: a hydrophobic core encapsulates PTX, while a polydopamine interlayer bridges the nanoparticle surface to a DNA hydrogel network via covalent conjugation and physical adsorption. Within this architecture, DNA duplexes load DOX through intercalation, and the polydopamine layer functions as both a stabilizer and a reduction-responsive gatekeeper. Upon exposure to the tumor microenvironment, the polydopamine layer undergoes pH-responsive structural rearrangement, inducing localized swelling that accelerates the release of hydrogel-entrapped drugs. FNAs confer three indispensable roles: 1) a targeting navigator directing tumor-specific accumulation through aptamer recognition, 2) a drug-loading matrix enabling precision loading of both agents, and 3) a microenvironment-responsive regulator controlling spatiotemporal release. This "all-in-one" functionalization strategy surmounts the mutual exclusivity of performance metrics in conventional carriers, redefining the paradigm of intelligent nanomedicine. Beyond addressing heterogeneous drug co-delivery, our modular design establishes an extensible platform for integrating theranostic functionalities (e.g., real-time imaging, immunomodulation), thereby advancing multimodal precision therapies in oncology.