Journal of Nanotheranostics

Immunotherapy can reduce treatment-related side effects but shows limited efficacy in “cold tumors,” whose immunosuppressive tumor immune microenvironment is characterized by abundant M2 macrophages and poor T cell infiltration. Because biopsy-based qualitative assessment of the tumor microenvironment is invasive and conventional imaging lacks functional information, this study aimed to develop an M2 macrophage-targeted theranostic agent enabling non-invasive photoacoustic (PA) imaging and pH-triggered cytotoxicity. A pullulan-based nanogel conjugated with mannose and near-infrared dye (IR-820) was further functionalized with the pH-responsive doxorubicin (DOX) prodrug, Aldoxorubicin, to develop Pullulan-mannose-IR820-Aldoxorubicin (PMID) nanogel. PMID was successfully synthesized, and the resulting self-assembled nanogels (<100 nm) exhibited a highly negative ζ-potential, near-infrared absorption peaks at 780 and 850 nm, and PA contrast comparable to IR-820 at 850 nm excitation. Dialysis studies demonstrated suppressed drug release at neutral pH (~20%) but accelerated release under acidic conditions, reaching ~80% within 48 h at pH 5.5, consistent with hydrazone hydrolysis and supporting tumor/lysosome-activated delivery. In RAW264.7 macrophages, PMID nanogel showed preferential uptake by M2-poralized versus M1-polarized macrophages, outperforming non-mannosylated PID nanogel and IR-820, and produced the strongest PA signal in M2 macrophage pellets. PMID nanogel also induced the highest concentration-dependent cytotoxicity in M2 macrophages, and microscopy indicated lysosomal accumulation of the nanogel with partial nuclear localization of released DOX. These findings support the use of PMID nanogel as M2 macrophage-targeted PA contrast agents and pH-responsive drug carriers with the potential to deplete immunosuppressive macrophages, modulate cold tumor microenvironments, and improve precision cancer theranostics.

Hydrogel-forming microneedles (HFMNs) are minimally invasive interfaces that access interstitial fluid (ISF) through skin penetration, swelling-mediated uptake, analyte diffusion, and hydrated sensor integration. This review examines HFMN architectures, skin–device interfaces, ISF transport, molecular-recognition and signal-transduction strategies, analytical performance, benchmarking, wear-associated failure modes, therapeutic monitoring, and translational priorities. The field has expanded from glucose sensing to metabolites, ions, hormones, proteins, nucleic acids, microbial and wound biomarkers, and therapeutic drugs, enabled by advances in hydrogel chemistry, conductive networks, nanostructured electrodes, catalysis, affinity recognition, molecular imprinting, optical readouts, and multiplexed wearables. Performance remains context dependent and requires physiological range, calibration stability, biofouling resistance, reliable insertion, validated ISF-reference correlations, and interpretable thresholds. Evidence is strongest in artificial matrices, ex vivo tissue, and animals, while human validation remains limited. Translation will require standardized mechanics and transport reporting, longer wear studies, sterilization-compatible chemistries, scalable manufacturing, and clinical validation. HFMNs may complement rather than replace blood-based diagnostics.

Theranostic nanoparticles, which integrate diagnostic imaging and therapeutic delivery within a single nanoplatform, represent a transformative paradigm in oncological nanomedicine. Despite substantial preclinical progress, the field faces persistent gaps in rational nanoparticle design informed by tumor biology, preclinical model fidelity, and clinical translation. This review critically synthesizes theranostic nanoparticle research across three underexplored domains. First, we examine tumor microenvironment features—reactive oxygen species dynamics, glutathione gradients, hypoxia, and proteasomal dysregulation—as mechanistic drivers of nanoparticle responsiveness. Second, we evaluate redox-responsive and proteasome-targeted nanoplatforms that exploit these cues for stimuli-triggered drug release and simultaneous imaging readout. Third, we address the unmet need for three-dimensional organoid and microfluidic tumor models as predictive preclinical testing environments, given the well-documented limitations of conventional two-dimensional cultures. Cancer subtype-specific applications are discussed for breast cancer, HPV-associated malignancies, colorectal cancer, and prostate cancer. Clinical translation barriers—including pharmacokinetic constraints, protein corona formation, immune clearance, anti-PEG antibodies, complement activation-related pseudoallergy, and FDA/EMA regulatory pathways—are addressed from a clinical oncology perspective. The review concludes with a research roadmap integrating proteomics-guided nanoparticle engineering, patient-derived organoid biobanks, and artificial intelligence-assisted design as priority areas for next-generation oncological theranostics.