Nanoconstructs for theranostic application in cancer: Challenges and strategies to enhance the delivery

The paper situates cancer as a leading global cause of mortality with rising incidence and deaths projected. It describes how nanotechnology offers new paradigms for diagnosis and therapy, enabling selective delivery and noninvasive tracking of therapeutic efficacy. Theranosis integrates imaging and therapy to apply precision medicine, with targeted and stimuli-responsive agents. Nanoconstructs, comprising nanoparticle cores and ligand shells, are presented as promising platforms to address chemotherapy drawbacks (toxicity, off-target biodistribution) but face issues of biocompatibility, uneven distribution, and lack of precision. The authors propose viewing delivery as autonomous and nonautonomous, incorporating blood flow and TME factors, and aim to review fundamental aspects, recent advancements, and strategies to enhance nanoconstruct delivery for cancer theranostics.

The review covers: (1) Cancer perspectives: genetic mutations (e.g., BRCA1/2, CHEK2, TP53), TME heterogeneity (ECM remodeling, immune components such as TILs, TAMs, CAFs), hypoxia, acidic pH, and their roles in resistance and relapse. Immunotherapy progress and limitations are noted (autoimmunity, variable efficacy, ECM barriers). (2) Nanoconstructs: defined as hard-core nanoparticles with soft ligand shells; benefits include specificity, enhanced deposition, reduced peripheral toxicity. Computational models (e.g., lattice-based, off-lattice, boundary tracking; individual cell-based) are used to simulate TME interactions, drug distribution, permeability, binding/unbinding, and optimize the 4S parameters (size, shape, surface, stiffness). (3) Building blocks: organic polymeric systems (PCL, PLL, PLGA, PPO), lipid-based systems; inorganic systems (iron oxide, gold, silver, black phosphorus) and hybrids. Black phosphorus features (optoelectronic, thermal, mechanical) enable photothermal and photodynamic effects via NIR and ROS generation. (4) Targeting mechanisms: passive (EPR-based), active (ligand-mediated, receptor targeting such as folate/transferrin), stimuli-responsive (internal pH, enzymes, redox; external light, magnetic field), and magnetic targeting via superparamagnetic nanoparticles under external fields. (5) Ligand selection: considerations include size, binding affinity, chemistry, immunogenicity, selectivity, production cost/time; strategies like PEGylation to enhance stability. (6) Theranostic applications: extensive examples of inorganic (e.g., BP with polymers/folate/albumin, MSNs with pH-responsive linkers and upconversion nanoparticles, CuS–silica hybrids labeled with 89Zr), polymeric (discoidal PLGA/PEG systems, FRET-enabled PEG-Pep-TPE/DOX for real-time release monitoring, PLGA-based radiodynamic therapy), dendrimeric (PAMAM hybrids for imaging and therapy) and composite systems combining chemo-, photo-, gene, and imaging modalities. (7) Image-guided systems: aptamer-conjugated SPIONs for MRI and drug delivery, QD-aptamer Bi-FRET constructs for simultaneous imaging and release tracking, pH-responsive micelles with photosensitizers for imaging-guided photodynamic therapy.

- Reframing targeting: Delivery modes are better classified as autonomous vs nonautonomous, capturing the influence of blood flow and TME on nanoconstruct fate. - Computational design: Modeling of tumor heterogeneity and transport (size, shape, surface, stiffness) can predict vessel wall interactions and optimize dosing, reducing time and cost. - Targeting strategies: Passive EPR, active ligand-receptor targeting, internal (pH, enzymes, redox) and external (light, magnetic field) stimuli enable spatiotemporal control of release and uptake. Magnetic targeting with superparamagnetic nanoparticles under strong fields provides high specificity with fewer side effects. - Building blocks: Organic (polymers, lipids, dendrimers), inorganic (iron oxide, gold, black phosphorus), and hybrids can be tuned for imaging and therapy. Black phosphorus enables NIR photothermal ablation and ROS-based photodynamic therapy; BP-PLL for Cas13a/crRNA delivery reduced Mcl-1 expression by 58.64% in vitro and suppressed cell activity. - Theranostic exemplars: - Upconversion/MSN systems with metal–phenolic networks enable real-time pH-triggered drug release monitoring and therapy. - CuS–mesoporous silica nanoshells with porphyrin labeled with 89Zr achieved tetramodal imaging and complete tumor elimination with enhanced blood retention and tumor deposition. - Hyaluronic acid-targeted, trio-responsive constructs (DOX + CuS + graphene oxide) showed high tumor deposition/retention, robust photothermal effect, ROS generation, and inhibited tumor growth. - PLGA radiodynamic nanoconstructs (verteporfin + perfluorooctylbromide) increased ROS under normoxic/hypoxic conditions, killed ~60% human pancreatic cancer cells in vitro, and suppressed tumor growth within 2 weeks. - Dendrimer–gold–curcumin with MUC-1 aptamer increased cytotoxicity and enabled CT-based imaging; PAMAM-DOX-F3 micelles with 64Cu showed rapid and persistent tumor accumulation on PET vs nontargeted controls. - Challenges quantified: EPR heterogeneity across tumor types; suggested permeability window cited at 600–800 nm for tumors vs 6–12 nm capillary pores and 5–6 nm renal filtration; protein corona formation, aggregation, shear degradation, and hydrolysis reduce tumor delivery; species/model differences limit translation and likely reduce human tumor delivery below therapeutic thresholds. - Enhancement strategies: Modulate TME (e.g., mitochondrial targeting with IONs–geldanamycin–MLS to inhibit TRAP-1), design effects of surface curvature on endosomal pathways, autonomous biohybrids (e.g., motile Salmonella carrying DOX liposomes) that self-propel and deliver intracellularly, and AI/ML for formulation design (predict encapsulation efficiency >90% via QSPR), toxicity, biocompatibility, and imaging analysis. - DNA nanorobotics: Aptamer-encoded logic-gated DNA origami devices for targeted, triggered release and biomarker sensing, enabling autonomous, imageable, computer-assisted delivery. - Image-guided delivery: Aptamer-SPIONs for MRI-targeted therapy (e.g., PSMA in prostate cancer), QD–aptamer Bi-FRET for tracking DOX release, PEG–polyacrylamide–iron oxide–photofrin systems targeted by F3 peptide for brain tumor imaging and PDT, and pH-sensitive micelles with protoporphyrin IX enabling fluorescence-guided ablation.

The review synthesizes how nanoconstruct design principles and targeting paradigms can improve the precision and efficacy of cancer theranostics. By accounting for TME-driven barriers and blood flow dynamics, the autonomous vs nonautonomous framework better aligns delivery strategies with biological constraints. Computational modeling informs rational design of the 4S parameters and predicts transport and binding in complex tumor settings, while stimuli-responsive materials add temporal control over release and activation. Case studies demonstrate that integrating imaging with therapy enables real-time monitoring, better biodistribution, and enhanced antitumor effects, including multi-modal imaging (e.g., tetramodal systems) and combined therapeutic modalities (chemo, photothermal, photodynamic, radiodynamic). Addressing EPR heterogeneity, protein corona effects, and model mismatch is critical; proposed strategies include TME modulation, biohybrid autonomous carriers, and AI/ML-guided formulation optimization to bridge preclinical–clinical translation gaps.

Nanoconstructs for cancer theranosis can enhance detection, enable precise and controlled delivery, and reduce off-target toxicity while allowing real-time monitoring of therapeutic response. A broad set of organic, inorganic, and hybrid platforms with exogenous and endogenous stimuli offer versatile control over drug release and targeting, especially when designed using computational models that incorporate TME features. Emerging technologies—including DNA origami nanorobots and AI/ML—hold promise to optimize design, predict performance, and accelerate personalized theranostics. Despite extensive preclinical progress, only a few systems have advanced clinically. Future work should focus on advanced multimodal materials, autonomous delivery mechanisms, robust image-guided platforms, and multidisciplinary, large-cohort clinical investigations to realize clinical translation.

The review highlights key limitations impeding translation: heterogeneity and unpredictability of the EPR effect across tumor types and stages; physical and biological barriers in the TME (dense ECM, abnormal vasculature, interstitial pressure, hypoxia, acidity) that hinder penetration and distribution; nanoparticle–blood interactions (protein corona, aggregation, shear, hydrolysis) reducing effective tumor accumulation; and poor translatability of animal models (differences in tumor burden relative to body weight and biology) leading to overestimation of human tumor delivery. Additional concerns include biocompatibility, uneven biodistribution, potential toxicity, immunogenicity of ligands, and manufacturing complexity/cost.