Aug 2026· Frontiers in Bioengineering and Biotechnology· Vol 14· 0 citations· 116 references
TL;DR
The evidence supports a conceptual transition from passive nanocarriers to programmable therapeutic systems capable of aligning therapeutic action with the spatial, temporal, and biological heterogeneity of tumors, but translation remains constrained by formulation complexity, incomplete standardization, limited long-term safety and biodistribution data, insufficient penetration into protected tumor niches, and the need for clinically relevant models that capture patient-level heterogeneity.
Abstract
Stimuli-responsive bioengineered platforms are redefining cancer therapy by shifting therapeutic design from systemic drug exposure toward context-dependent activation within malignant tissue. These systems are engineered to sense and respond to tumor-associated or externally applied cues, including acidic pH, redox imbalance, hypoxia, enzymatic activity, reactive oxygen species, temperature variation, light, ultrasound, and magnetic fields. Across the reviewed evidence, their principal value lies not merely in drug encapsulation but in the coordinated control of localization, release, intracellular access, multimodal therapy, microenvironment modulation, and safety. The field encompasses diverse architectures, including biomacromolecular nanoparticles, hydrogels, nanogels, polymeric micelles, prodrug assemblies, lipid-based systems, mesoporous silica, metal–organic frameworks, carbon-based materials, magnetic nanocomposites, and hybrid inorganic–organic constructs. These platforms have been validated in multiple cancer models through assays of uptake, cytotoxicity, apoptosis, spheroid penetration, tumor suppression, metastasis, recurrence, immune activation, stromal remodeling, and systemic tolerability. Collectively, the evidence supports a conceptual transition from passive nanocarriers to programmable therapeutic systems capable of aligning therapeutic action with the spatial, temporal, and biological heterogeneity of tumors. However, translation remains constrained by formulation complexity, incomplete standardization, limited long-term safety and biodistribution data, insufficient penetration into protected tumor niches, and the need for clinically relevant models that capture patient-level heterogeneity. Future progress will depend on rationally simplified architectures, quantitative stimulus–response validation, scalable manufacturing, integrated safety assessment, and biomarker-guided selection of platforms matched to defined tumor microenvironments. Stimuli-responsive bioengineering therefore represents a promising, although still maturing, foundation for safer, more selective, and more mechanistically coordinated precision cancer therapy.
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype lacking effective targeted therapies. Its tumor microenvironment (TME) exhibits distinct features, including acidity, redox imbalance, elevated reactive oxygen species (ROS), and hypoxia, which provide exploitable triggers for targeted drug delivery. Stimuli-responsive polymeric nanocarriers have emerged as promising platforms that enable spatiotemporally controlled and site-specific therapeutic release in response to these endogenous cues, as well as exogenous stimuli such as temperature and light. These systems improve drug accumulation, penetration, and therapeutic efficacy while reducing systemic toxicity. Unlike previous reviews that broadly discuss nanocarriers in cancer therapy, this review focuses on the structure–function relationships of TME-responsive polymeric systems in TNBC and their translational limitations. We summarize recent advances in pH-, redox-, ROS-, hypoxia-, photo- and temperature-responsive polymers, highlighting their design strategies and therapeutic applications. Key challenges, including stimulus heterogeneity, limited in vivo validation, and clinical translation barriers, are also discussed. This review provides a concise framework for the rational design of programmable, multi-responsive polymeric nanomedicines for TNBC therapy.
Adnan Murad Bhayo, Ying Li, Alaa R. Aboushanab et al.· Pharmaceutics· 0 citations
Cancer remains a major global health challenge, and the limitations of conventional therapies, including systemic toxicity, drug resistance, and poor tumor selectivity, continue to drive the development of advanced nanomedicine strategies. In this context, nanocarriers offer promising opportunities to improve pharmacokinetics, enhance tumor accumulation, and enable controlled or stimuli-responsive drug release. Among them, inorganic nanoparticles (NPs) have gained considerable attention because of their structural stability, tunable surface chemistry, and multifunctional capabilities. Their performance depends on a structure–property–function relationship in which composition, morphology, porosity, degradability, and surface characteristics strongly influence interactions at the nano–bio interface. This review examines the main classes of nanoplatforms currently explored for cancer therapy, including inorganic, polymeric, lipid-based, and hybrid organic–inorganic systems. Particular attention is given to the trade-offs that define each platform in terms of loading capacity, biodegradability, multifunctionality, and translational potential. The discussion also highlights the role of predictive biological models, emphasizing that 3D spheroids, organoids, and organ-on-chip systems provide more realistic insights than conventional 2D assays for evaluating tumor penetration and microenvironment-responsive delivery. In addition, the review considers emerging directions in AI-guided nanoparticle engineerization design and natural-compound-based nanomedicines, both of which are expanding the therapeutic landscape. Overall, the field is moving toward more integrated, application-specific, and clinically translatable nanomedicine platforms capable of addressing the complex biological barriers of cancer treatment.
C. Boncristiani, F. Baldassarre, Khadija Eddahaoui et al.· Materials· 0 citations
Hypoxia, immunosuppression, and pronounced heterogeneity within the tumor microenvironment (TME) hinder the effectiveness of cancer therapies. Engineered bacteria–nanomaterial hybrid systems have emerged as a promising approach to address these challenges. Bacterial chassis provide active tumor targeting, deep tissue penetration, and in situ proliferation, facilitating the precise delivery of immunomodulators. Concurrently, nanomaterials interfaced with these living carriers can be activated by external physical stimuli, inducing photothermal, photodynamic, sonodynamic, and magnetothermal effects within solid tumors. These interactions promote immunogenic cell death (ICD) and enable real-time monitoring. Recent advances in synthetic biology and nanotechnology have led to the development of an expanding range of preclinical biohybrid platforms, while several related components, including bacterial therapeutics, bacterial derivatives, and physically activated nanomedicine platforms, have progressed into clinical evaluation. This review first explores the origins and roles of tumor-associated bacteria. It then summarizes strategies for engineering bacteria–nanomaterial hybrid systems. Subsequently, this review examines how physical stimuli enhance targeting, remodel the TME, and amplify antitumor immunity. Finally, safety, manufacturing, and regulatory challenges impacting clinical translation are discussed. Overall, these platforms offer a potentially powerful framework for precision cancer immunotherapy. However, successful clinical translation will require stronger evidence regarding safety, controllability, manufacturing consistency, and therapeutic efficacy.
Jiayue Lin, Ming An, Yuxin Dai et al.· Research· 0 citations
The cancer is still one of the world’s biggest public health problems due to its diversity (tumor), multiresistance, and non-specific delivery by drugs like chemotherapy. Oncological precision medicine is changing treatment paradigms towards targeted therapies with high specificity and low-toxicity options for patients’ use. Among them, stimuli-responsive nanocarriers are smart drug delivery systems that release drugs in response to endogenous stimuli, pH, redox potential, enzymes, reactive oxygen species, and hypoxia, or exogenous stimuli (light, magnetic fields, ultrasound, and temperature). The intelligent nanovehicles utilize properties specific to tumors’ environment that allow precise targeting with targeted delivery mechanisms, resulting in better penetration rates as well as lower toxicity levels within tissues. Nanotech innovations allow for multi-functional devices that incorporate anticancer drugs as well as genetic treatments; immune responses are also incorporated to provide diagnostics on one device platform. Though there are some favorable results from laboratory studies as well as successful trials with nanoparticles medicines, there are problems such as production difficulties for drugs’ approval process, variation among individuals due to genetics, etc. The paper reviews current developments concerning stimulus-responsive nanoparticles; it also describes how these agents work as a means to treat cancers precisely.
C. J. Jiflin, Mohana Sundaram Somasundharam Pushpanathan, Jeevitha Dhayalan et al.· BOHR Journal of Pharmaceutic...· 0 citations
Although strategic combination of cuproptosis and chemotherapy is emerging as a promising strategy against triple-negative breast cancer (TNBC), current drug delivery systems remain considerable challenges in achieving co-delivery of different formulas, such as complex nanocarrier design, limited drug loading capacity, and insufficient tumor targeting. Herein, cancer cell membrane-camouflaged, self-assembled nanoparticles (DCM@CCM) were fabricated for precision combination therapy against TNBC. In the strategy, the carrier-free self-assembled nanoparticles were one-pot fabricated by co-assembling copper ions (Cu2+), doxorubicin (DOX), and methotrexate (MTX) via hydrogen bonds, π-π stacking and metal-ligand coordination effect, followed by in situ camouflaging with cancer cell membranes. Benefiting from the homologous targeting effect, the developed DCM@CCM could specifically target tumor cells, promoting their cellular uptake. Following internalization into tumor cells, the DCM@CCM disassembled in response to a weakly acidic tumor microenvironment, releasing Cu2+, DOX, and MTX. Importantly, the Cu2+ was reduced to Cu+ by depleting intracellular glutathione, which not only activated cuproptosis but also catalyzed the endogenous hydrogen peroxide into highly toxic hydroxyl radicals via a Fenton-like reaction, resulting in mitochondrial dysfunction. Simultaneously, both DOX and MTX disrupted DNA synthesis to trigger cell apoptosis. Both in vitro and in vivo experiments indicated that DCM@CCM exhibited potent cytotoxicity against TNBC cells and effectively suppressed tumor growth in heterotopic tumor models with minimal side effects. Overall, our study not only provides a promising strategy for precision combination therapy against TNBC but also expands insight for developing nanoscale self-assembly-enabled nanomedicine.
Qian Liu, Xinyi Tao, Yawen Luo et al.· ACS Applied Bio Materials· 0 citations
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